Processes for the diastereoselective separation of nucleoside analogue synthetic intermediates

ABSTRACT

The present invention relates to highly diastereoselective processes for production of cis-nucleosides and nucleoside analogues and derivatives in high optical purity and intermediates useful in those processes.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 08/142,387, filedJun. 13, 1994, which is a continuation-in-part of application Ser. No.07/703,379, filed May 21, 1991, now abandoned.

FIELD OF THE INVENTION

The present invention relates to diastereoselective processes forpreparing optically active cis-nucleosides and nucleoside analogues andderivatives. The novel processes of this invention allow thestereo-controlled synthesis of a given enantiomer of a desiredcis-nucleoside or nucleoside analogue or derivative in high opticalpurity. This invention also relates to novel intermediates useful in theprocesses of this invention.

BACKGROUND OF THE INVENTION

Nucleosides and their analogues and derivatives are an important classof therapeutic agents. For example, a number of nucleosides have shownantiviral activity against retroviruses such as human immunodeficiencyvirus (HIV), hepatitis B virus (HBV) and human T-lymphotropic virus(HTLV) (PCT publication WO 89/04662 and European Patent publication0349242 A2). Among the nucleosides shown to have antiviral activity are3'-azido-3'-deoxythymidine (AZT), 2'3'-dideoxy-cytidine (DDC),2-hydroxymethyl-5-(cytosin-1'-yl)-1,3-oxathiolane and2-hydroxymethyl-4-(guanin-9'-yl)-1,3-dioxolane (European Patentpublication 0382526 A2 and European Patent publication 0377713 A2).

Most nucleosides and nucleoside analogues and derivatives contain atleast two chiral centers (shown as * in formula (A)), and exist in theform of two pairs of optical isomers (i.e., two in the cis-configurationand two in the trans-configuration). However, generally only thecis-isomers exhibit useful biological activity. ##STR1## Differentenantiomeric forms of the same cis-nucleoside may, however, have verydifferent antiviral activities. M. M. Mansuri et al., "Preparation OfThe Geometric Isomers Of DDC, DDA, D4C and D4T As Potential Anti-HIVAgents", Bioorg.Med.Chem.Lett., 1 (1), pp. 65-68 (1991). Therefore, ageneral and economically attractive stereoselective synthesis of theenantiomers of the biologically active cis-nucleosides is an importantgoal.

Many of the known processes for producing optically active nucleosidesand their analogues and derivatives modify naturally occurring (i.e.,optically active) nucleosides by altering the base or by altering thesugar via reductive procedures such as deoxygenation or radicalinitiated reductions. C. K. Chu et al., "General Synthesis Of2',3'-Dideoxynucleosides And 2',3'-Didehydro-2',3'-Dideoxynucleosides,"J.Org.Chem., 54, pp. 2217-2225 (1989). These transformations involvemultiple steps, including protection and deprotection and usually resultin low yields. Moreover, they begin with and maintain the opticalactivity of the starting nucleoside. Thus, the nucleosides produced bythese processes are limited to specific analogues of the enantiomericform of the naturally occurring nucleoside. In addition, theseprocedures require the availability of the naturally occurringnucleoside, often an expensive starting material.

Other known processes for producing optically active nucleosides rely onconventional glycosylation procedures to add the sugar to the base.These procedures invariably give anomeric mixtures of cis- andtrans-isomers which require tedious separation and result in loweryields of the desired biologically active cis-nucleoside. Improvedglycosylation methods designed to yield only the cis-nucleoside requireaddition of a 2'- or 3'-substituent to the sugar. Because the 2'- or3'-substituent is only useful in controlling cis-nucleoside synthesis inone configuration (when the 2' or 3' substituent is trans- to the 4'substituent), multiple steps are required to introduce this substituentin the proper configuration. The 2'- or 3'-substituent must then beremoved after glycosylation, requiring additional steps. L. Wilson andD. Liotta, "A General Method For Controlling Stereochemistry In TheSynthesis Of 2'-Deoxyribose Nucleosides", Tetrahedron Lett., 31, pp.1815-1818 (1990). Furthermore, to obtain an optically pure nucleosideproduct, the starting sugar must be optically pure. This also requires aseries of time-consuming syntheses and purification steps.

SUMMARY OF THE INVENTION

The present invention overcomes the difficulties and shortcomings of theprior art and provides processes for producing optically activecis-nucleosides (1,3-oxathiolanes, 2,4-dioxolanes, and 1,3-dithiolanes)or nucleoside analogues and derivatives of formula (I) ##STR2## whereinW is S, S═O, SO₂, or O;

X is S, S═O, SO₂, or O;

R₁ is hydrogen or acyl; and

R₂ is a purine or pyrimidine base or an analogue or derivative thereof.

The processes of this invention comprise the step of glycosylating adesired purine or pyrimidine base or analogue or derivative thereof withan intermediate of formula (IIa) or (IIb) ##STR3## wherein R₃ is asubstituted carbonyl or carbonyl derivative and L is a leaving group.Glycosylation is accomplished using a Lewis acid of the formula (III)##STR4## wherein R₅, R₆, R₇, and R₈ are defined below and the resultingintermediate is reduced to give a nucleoside or nucleoside analogue orderivative of formula (I).

The processes of this invention have the advantages of allowingpreparation of a nucleoside of formula (I) (or analogues or derivativesthereof) without using expensive starting materials, cumbersomeprotection and deprotection steps or addition and removal of 2'- or3'-substituents. The processes of this invention produce nucleosides inhigh yields, with high purity and high optical specificity. Theprocesses of this invention have the further advantage of generatingnucleosides whose stereoisomeric configuration can be easily controlledsimply by the selection of the appropriate starting materials.

DETAILED DESCRIPTION OF THE INVENTION

In the processes for preparing optically active compounds of thisinvention in a configurational- and diastereo-selective manner, thefollowing definitions are used:

R₂ is a purine or pyrimidine base or an analogue or derivative thereof.

A purine or pyrimidine base is a purine or pyrimidine base found innaturally occurring nucleosides. An analogue thereof is a base whichmimics such naturally occurring bases in that their structures (thekinds of atoms and their arrangement) are similar to the naturallyoccurring bases but may either possess additional or lack certain of thefunctional properties of the naturally occurring bases. Such analoguesinclude those derived by replacement of a CH moiety by a nitrogen atom,e.g., 5-azapyrimidines such as 5-azacytosine) or vice versa (e.g.,7-deazapurines, such as 7-deazaadenine or 7-deazaguanine) or both (e.g.,7-deaza, 8-azapurines). By derivatives of such bases or analogues aremeant those bases wherein ring substituents are either incorporated,removed, or modified by conventional substituents known in the art,e.g., halogen, hydroxyl, amino, C₁₋₆ alkyl. Such purine or pyrimidinebases, analogues and derivatives are well known to those skilled in theart.

A "nucleoside analogue or derivative" is a 1,3-oxathiolane,2,4-dioxolane or 1,3-dithiolane which has been modified in any of thefollowing or combinations of the following ways: base modifications,such as addition of a substituent (e.g., 5-fluorocytosine) orreplacement of one group by an isosteric group (e.g., 7-deazaadenine);sugar modifications, such as substitution of the C-2 and C-3 hydroxylgroups by any substituent, including hydrogen (e.g.,2',3'-dideoxynucleosides); alteration of the site of attachment of thesugar to the base (e.g., pyrimidine bases usually attached to the sugarat the N-1 site may be, for example, attached at the N-3 or C-6 site andpurines usually attached at the N-9 site may be, for example, attachedat N-7); alteration of the site of attachment of the base to the sugar(e.g., the base may be attached to the sugar at C-2, such as iso-DDA);or alteration of configuration of the sugar-base linkage (e.g., cis ortrans configurations).

R₃ is a carbonyl substituted with hydrogen, hydroxyl, trialkylsilyl,trialkylsiloxy, C₁₋₃₀ alkyl, C₇₋₃₀ aralkyl, C₁₋₃₀ alkoxy, C₁₋₃₀ amine(primary, secondary or tertiary), C₁₋₃₀ thiol; C₆₋₂₀ aryl; C₁₋₂₀alkenyl; C₁₋₂₀ alkynyl; 1,2-dicarbonyl, such as ##STR5## substitutedwith C₁₋₆ alkyl or C₆₋₂₀ aryl; anyhdrides such as ##STR6## substitutedwith C₁₋₆ alkyl or C₆₋₂₀ aryl; azomethine substituted at nitrogen withhydrogen, C₁₋₂₀ alkyl or C₁₋₁₀ alkoxy or C₁₋₁₀ dialkyiamino or at carbonwith hydrogen, C₁₋₂₀ alkyl, or C₁₋₂₀ alkoxy; thiocarbonyl (C═S)substituted with hydroxyl, C₁₋₂₀ alkoxy, or C₁₋₂₀ thiol; a homologue ofcarbonyl, e.g., ##STR7## a homologue of thiocarbonyl, e.g., ##STR8## ora homologue of azomethine, such as ##STR9##

The preferred substituted carbonyl/carbonyl derivatives arealkoxycarbonyls, such as methyl, ethyl, isopropyl, t-butyl and menthyl;carboxyls, diethylcarboxamide; pyrrolidine amide; methyl ketone andphenyl ketone. The more preferred substituted carbonyl/carbonylderivatives are esters and carboxyls and the most preferred are esters.

R₄ is a chiral auxiliary. The term "chiral auxiliary" describesasymmetric molecules that are used to effect the chemical resolution ofa racemic mixture. Such chiral auxiliaries may possess one chiral centersuch as methylbenzylamine or several chiral centers such as menthol. Thepurpose of the chiral auxiliary, once built into the starting material,is to allow simple separation of the resulting diastereomeric mixture.See, for example, J. Jacques et al., Enantiomers, Racemates AndResolutions, pp. 251-369, John Wiley & Sons, New York (1981).

R₅, R₆ and R₇ are independently selected from the group consisting ofhydrogen, C₁₋₂₀ alkyl (e.g., methyl, ethyl, t-butyl), optionallysubstituted by halogens (F, Cl, Br, I), C₆₋₂₀ alkoxy (e.g., methoxy) orC₆₋₂₀ aryloxy (e.g., phenoxy); C₇₋₂₀ aralkyl (e.g., benzyl), optionallysubstituted by halogen, C₁₋₂₀ alkyl or C₁₋₂₀ alkoxy (e.g.,p-methoxybenzyl); C₆₋₂₀ aryl (e.g., phenyl), optionally substituted byhalogens, C₁₋₂₀ alkyl or C₁₋₂₀ alkoxy; trialkylsilyl; halogens (F, Cl,Br, I).

R₈ is selected from the group consisting of halogen (F, Cl, Br, I);C₁₋₂₀ sulphonate esters, optionally substituted by halogens (e.g.,trifluoromethane sulphonate); C₁₋₂₀ alkyl esters, optionally substitutedby halogen (e.g., trifluoroacetate); polyvalent halides (e.g.,triiodide); trisubstituted silyl groups of the general formula(R₅)(R₆)(R₇)Si (wherein R₅, R₆, and R₇ are as defined above); saturatedor unsaturated selenenyl C₆₋₂₀ aryl; substituted or unsubstituted C₆₋₂₀arylsulfenyl; substituted or unsubstituted C₁₋₂₀ alkoxyalkyl; andtrialkylsiloxy.

L is a "leaving group", i.e., an atom or a group which is displaceableupon reaction with an appropriate purine or pyrimidine base, with orwithout the presence of a Lewis acid. Suitable leaving groups includeacyloxy groups, alkoxy groups, e.g., alkoxy carbonyl groups such asethoxy carbonyl; halogens such as iodine, bromine, chlorine, orfluorine; amido; azido; isocyanato; substituted or unsubstituted,saturated or unsaturated thiolates, such as thiomethyl or thiophenyl;substituted or unsubstituted, saturated or unsaturated seleno,seleninyl, or selenonyl compounds, such as phenyl selenide or alkylselenide.

A suitable leaving group may also be --OR, where R is a substituted orunsubstituted, saturated or unsaturated alkyl group, e.g., C₁₋₆ alkyl oralkenyl group; a substituted or unsubstituted aliphatic or aromatic acylgroup, e.g., a C₁₋₆ aliphatic acyl group such as acetyl and asubstituted or unsubstituted aromatic acyl group such as benzoyl; asubstituted or unsubstituted, saturated or unsaturated alkoxy or aryloxycarbonyl group, such as methyl carbonate and phenyl carbonate;substituted or unsubstituted sulphonyl imidazolide; substituted orunsubstituted aliphatic or aromatic amino carbonyl group, such as phenylcarbamate; substituted or unsubstituted alkyl imidiate group such astrichloroacetamidate; substituted or unsubstituted, saturated orunsaturated phosphonate, such as diethylphosphonate; substituted orunsubstituted aliphatic or aromatic sulphinyl or sulphonyl group, suchas tosylate; or hydrogen.

As used in this application, the term "alkyl" represents a substituted(by a halogen, hydroxyl or C₆₋₂₀ aryl) or unsubstituted straight chain,branched chain, or cyclic hydrocarbon moiety having 1 to 30 carbon atomsand preferably, from 1 to 6 carbon atoms.

The terms "alkenyl" and "alkynyl" represent substituted (by a halogen,hydroxyl or C₆₋₂₀ aryl) or unsubstituted straight, branched or cyclichydrocarbon chains having 1 to 20 carbon atoms and preferably from 1 to5 carbon atoms and containing at least one unsaturated group (e.g.,allyl).

The term "alkoxy" represents a substituted or unsubstituted alkyl groupcontaining from 1 to 30 carbon atoms and preferably from 1 to 6 carbonatoms, wherein the alkyl group is covalently bonded to an adjacentelement through an oxygen atom (e.g., methoxy and ethoxy).

The term "amine" represents alkyl, aryl, alkenyl, alkynyl, or aralkylgroups containing from 1 to 30 carbon atoms and preferably 1 to 12carbon atoms, covalently bonded to an adjacent element through anitrogen atom (e.g., pyrrolidine). They include primary, secondary andtertiary amines and quaternary ammonium salts.

The term "thiol" represents alkyl, aryl, aralkyl, alkenyl or alkynylgroups containing from 1 to 30 carbon atoms and preferably from 1 to 6carbon atoms, covalently bonded to an adjacent element through a sulfuratom (e.g., thiomethyl).

The term "aryl" represents a carbocyclic moiety which may be substitutedby at least one heteroatom (e.g., N, O, or S) and containing at leastone benzenoid-type ring and preferably containing from 6 to 15 carbonatoms (e.g., phenyl and naphthyl).

The term "aralkyl" represents an aryl group attached to the adjacentatom by an alkyl (e.g., benzyl).

The term "alkoxyalkyl" represents an alkoxy group attached to theadjacent group by an alkyl group (e.g., methoxymethyl).

The term "aryloxy" represents a substituted (by a halogen,trifluoromethyl or C₁₋₅ alkoxy) or unsubstituted aryl moiety covalentlybonded through an oxygen atom (e.g., phenoxy).

The term "acyl" refers to a radical derived from a carboxylic acid,substituted (by a halogen (F, Cl, Br, I), C₆₋₂₀ aryl or C₁₋₆ alkyl) orunsubstituted, by replacement of the --OH group. Like the acid to whichit is related, an acyl radical may be aliphatic or aromatic, substituted(by a halogen, C₁₋₅ alkoxyalkyl, nitro or O₂) or unsubstituted, andwhatever the structure of the rest of the molecule may be, theproperties of the functional group remain essentially the same (e.g.,acetyl, propionyl, isobutanoyl, pivaloyl, hexanoyl, trifluoroacetyl,chloroacetyl, and cyclohexanoyl).

A key feature of the processes of this invention is the use of asubstituted carbonyl or carbonyl derivative as R₃ instead of a protectedhydroxymethyl group as previously described in the art. Surprisingly,the substituted carbonyl or carbonyl derivative is not cleaved byexposure to a Lewis acid, as would have been expected by one of skill inthe art when a Lewis acid of formula (III) is added to a mixture ofsilylated purine or pyrimidine base and the chiral auxiliary-sugarcompound obtained in Step 3. Instead, the substituted carbonyl/carbonylderivative in the intermediate of formula (VI) forces the purine orpyrimidine base (R₂) to add in the cis-configuration relative to thesubstituted carbonyl/carbonyl derivative group. Without a substitutedcarbonyl or carbonyl derivative attached to C4' (for example, when ahydroxymethyl group is instead used), the coupling procedures describedin Step 4 will result in a mixture of cis- and trans-isomers.

Another key feature of the processes of this invention is the choice ofLewis acid. The Lewis acids used in the preparation of compounds offormula (I) have the general formula (III) ##STR10## wherein R₅, R₆, R₇and R₈ are as defined previously. These Lewis acids may be generated insitu or prepared using any method known in the art (e.g., A. H. Schmidt,"Bromotrimethylsilane and Iodotrimethylsilane-Versatile Reagents forOrganic Synthesis", Aldrichimica Acta, 14, pp. 31-38 (1981). Thepreferred Lewis acids of this invention are iodotrimethylsilane andtrimethylsilyl triflate. The preferred R₅, R₆ and R₇ groups are methylor iodine. The most preferred R₅, R₆ and R₇ group is methyl. Thepreferred R₈ groups are iodine, chlorine, bromine or sulphonate esters.The most preferred R₈ groups are iodine and trifluoromethane sulphonate.

In the preferred process of this invention, illustrated in Schemes 1 and2, cis- and trans-isomers of a sugar of formula (II) ##STR11## areseparated by fractional crystallization and the desired configurationalisomer selected. The selected cis- or the trans-isomer may then beresolved chemically, e.g., using a chiral auxiliary, enzymatically, orby other methods known in the art. The pure diastereomer is then coupledto a silylated purine or pyrimidine base in the presence of a Lewis acidto afford an optically active nucleoside of cis-configuration which issubsequently reduced to give a nucleoside of formula (I).

Schemes 1A and lB depict this preferred process as applied to any1,3-oxathiolane, 2,4-dioxolane or 1,3-dithiolane. ##STR12##

The various steps as illustrated in Schemes 1A and 1B may be brieflydescribed as follows:

Step 1: The starting carbonyl-sugar of formula (IV) can be prepared byany method known in the art. E.g., J. M. Mcintosh et al.,"2-Mercaptoaldehyde Dimers and 2,5-Dihydrothiophenes from1,3-oxathiolan-5-ones", Can. J. Chem., 61, pp. 1872-1875 (1983). Thecarbonyl group of this starting compound is reduced chemoselectivelywith a suitable reducing agent, such as disiamylborane to give the cis-and trans-isomers of formula (V). Ordinarily, less cis-isomer isproduced than trans.

Step 2: The hydroxyl group in the intermediate of formula (V) is readilyconverted to a leaving group by any method known in the art (e.g., T. W.Greene Protective Groups In Organic Synthesis, pp. 50-72, John Wiley &Sons, New York (1981)) to give the novel intermediates of formula (II).

This anomeric mixture is then separated by fractional crystallizationinto the two configurational isomers. The solvent may be adjusted toselect for either the cis- or trans-isomer. D. J. Pasto and C. R.Johnson, Organic Structure Determination, pp. 7-10, Prentice-Hall, Inc.,New Jersey (1969).

Step 3: Either the cis- (Scheme 1A) or trans-isomer (Scheme 1B) offormula (II) is chemically resolved using a chiral auxiliary (R₄). Asuitable chiral auxiliary is one of high optical purity and where themirror image is readily available, such as d- and 1-menthol. Theresulting diastereomers of formula (VI) are easily separated byfractional crystallization. Alternatively, either the cis- or thetrans-isomer may be resolved enzymatically or by other methods known inthe art. Jacques et al., Enantiomers, Racemates And Resolutions, pp.251-369, John Wiley & Sons, New York (1981).

The optical purity of the diastereomer (VI, VII or I) can be determinedby chiral HPLC methods, specific rotation measurements and NMRtechniques. As a general rule, if the opposite enantiomer is desired, itmay be obtained by using the mirror image of the chiral auxiliaryinitially employed. For example, if the chiral auxiliary d-mentholproduces a (+)-enantiomer nucleoside, its mirror image, 1-menthol, willproduce the (-)-enantiomer.

Step 4: A previously silylated (or silylated in situ) purine orpyrimidine base or analogue or derivative thereof is then glycosylatedwith the resulting pure diastereomer in the presence of a Lewis acid offormula (III), such as iodotrimethylsilane (TMSI) or trimethylsilyltriflate (TMSOTf), to give a nucleoside of cis-configuration of formula(VII). This nucleoside is optically active and is substantially free ofthe corresponding trans-isomer (i.e., it contains less than 20%,preferably no more than 10% and more preferably no more than 5% of thetrans-isomer).

The preferred silylating agent for pyrimidine bases aret-butyldimethylsilyl triflate 1,1,1,3,3,3 hexamethyldisilazane andtrimethylsilyl triflate. It is believed that the bulky t-butyl groupincreases yields by weakening the interaction between the Lewis acid andsilylated pyrimidine base.

The preferred method of mixing reagents in Step 4 is to first add thechiral auxiliary-sugar of formula (VI) to the silylated purine orpyrimidine base. The Lewis acid of formula (III) is then added to themixture.

Step 5: The cis-nucleoside obtained in Step 4 may then be reduced withan appropriate reducing agent to remove the chiral auxiliary and give aspecific stereoisomer of formula (I). The absolute configuration of thisstereoisomer corresponds to that of the nucleoside intermediate offormula (VII). As shown in Scheme 1, either the cis- (Scheme 1A) or thetrans-isomers (Scheme lB) obtained in Step 2 will yield a cis endproduct.

Schemes 2A and 2B illustrate the application of the process of Schemes1A and 1B to the synthesis of the enantiomers ofcis-2-hydroxymethyl-5-(cytosin-1'-yl)-1,3-oxathiolanes. Although thisprocess is illustrated using specific reagents and starting materials,it will be appreciated by one of skill in the art that suitableanalogous reactants and starting materials may be used to prepareanalogous compounds. ##STR13##

The various steps illustrated in Schemes 2A and 2B may be brieflydescribed as follows:

Step 1: A mercaptoacetaldehyde monomer, preferably produced from adimer, such as 2,5-dihydroxy-1,4-dithiane, in an appropriate solvent(preferably t-butylmethyl ether) is reacted with glyoxylic acid to giveexclusively the trans-hydroxy acid of formula (VIII).

Step 2: The acid of formula (VIII) is reacted with an acid chloride,such as acetyl chloride in the presence of pyridine and an acylationcatalyst, such as 4-dimethylaminopyridine, or preferably with an acidanhydride such as acetic anhydride in the presence of acetic acid and anacylation catalyst, such as sulfuric acid, to give a diastereomericmixture of cis- and trans-acetoxy acids of formula (IX).

The racemic diastereomeric acid mixture obtained in Step 2 isfractionally crystallized using any combination of solvents (preferablybenzene and ether) to give exclusively either the cis- or thetrans-acetoxy acid of formula (IX) each as a racemic mixture.

Step 3: Either the cis- or the trans-acetoxy acid of formula (IX) isreacted with an appropriate chiral auxiliary preferably, 1-menthol ord-menthol, in a suitable organic solvent, such as dichloromethane, usingan activating agent, such as dicyclohexylcarbodiimide, and anesterification catalyst, such as 4-dimethylaminopyridine, to give adiastereomeric mixture of the cis- or trans-esters respectively.

Alternatively, the compound of formula (IX) may be converted to an acidchloride by any means known in the art, such as with oxalyl chloride inan appropriate solvent, e.g., dichloromethane or N₁ N-dimehylformamide.The acid chloride is then reacted with a chiral auxiliary in a suitableorganic solvent using an esterification catalyst.

Step 4: The above diastereomeric mixture of either the cis- or thetrans-esters is fractionally crystallized using any combination ofsolvents (preferably ether and petroleum ether (40°-60° C.)) preferablyat low temperature to give exclusively the cis- or the trans-acetoxymenthyl ester of formula (X), respectively.

Step 5: Either the cis- or the trans-acetoxy compound of formula (X) isreacted with cytosine or other purine or pyrimidine base or analoguethereof. The purine or pyrimidine base or analogue is preferablypreviously silylated with hexamethyldisilazane or more preferablysilylated in situ with t-butyldimethylsilyl triflate in a compatibleorganic solvent, such as dichloromethane containing a hindered basepreferably 2,4,6-collidine. A Lewis acid of formula (III), preferablyiodotrimethylsilane or trimethylsilyl triflate, is then added to givethe cis-compound of formula (XI) in a highly diastereoselective manner.

Step 6: The optically active cis-nucleoside of formula (XI) is reducedstereospecifically with a reducing agent preferably lithiumtriethylborohydride or more preferably lithium aluminum hydride in anappropriate solvent such as tetrahydrofuran or diethyl ether to give thecompound of formula (XII) and menthol.

A second process for the diastereoselective synthesis of compounds offormula (I) is illustrated by Schemes 3A and 3B and 4A and 4B. In theprocess of Schemes 3A and 3B carbonyl-sugar with an R₃ substituent at C₄' is reacted with a chiral auxiliary (R₄) to give a diastereomericmixture of two optically active chiral auxiliary sugars. The actualdiastereomer produced depends on whether the (+) or (-) chiral auxiliaryis used. This optically active mixture may be chemoselectively reducedand the resulting hydroxyl group converted to a leaving group to afforda diastereomeric mixture of four chiral auxiliary-sugars, two in thecis- configuration and two in the trans-configuration (Scheme 3B).Subsequent fractional crystallization gives a single diastereomer.

Alternatively, the optically active mixture of chiral auxiliary-sugarsmay first by separated by chromatography or fractional crystallizationand then reduced and the resulting hydroxyl group converted to a leavinggroup (Scheme 3A). Subsequent fractional crystallization yields anydesired diastereomer. The solvent may be adjusted to select for eitherthe cis- or the trans-isomer. Each isolated optically activediastereomer-may be carried on further to compounds of formula (I) in amanner analogous to that described in Schemes 1 and 2.

Schemes 3A and 3B depict the second process of this invention as appliedto any 1,3-oxathiolane, 2,4-dioxolane or 1,3-dithiolane. ##STR14##

The various steps involved in the synthesis of the nucleosides offormula (I) as depicted in Schemes 3A may be briefly described asfollows:

Step 1: The starting material of formula (IV), prepared by any methodknown in the art, is reacted with a chiral auxiliary (see, e.g., T. W.Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons,New York (1981) to yield a mixture of two diastereomers of formula(XIII). The particular mixture produced will depend on which chiralauxiliary (+ or -) is used.

Step 2: The mixture of two diastereomers of formula (XIII) is separatedby fractional crystallization or chromatography to yield onediastereomer of formula (XIII).

Step 3: The single isomer of formula (XIII) is chemoselectively reducedby a suitable reducing agent, such as disiamylborane to give a mixtureof two diastereomers of formula (XIV).

Step 4: The hydroxyl groups of the two diastereomers of formula (XIV)are converted to leaving groups by any method known in the art to give amixture of two diastereomers of formula (VI).

Step 5: Either the cis- or trans-isomer is separated out of the mixtureof two diastereomers of formula (VI), as obtained in Step 4, byfractional crystallization or chromatography. The solvent may beadjusted to select for the cis- or trans-isomer.

Step 6: The single diastereomer of formula (VI) is reacted withpreviously silylated (or silylated in situ) purine or pyrimidine base oranalogue or derivative. Then, addition of a Lewis acid of formula (III),such as iodotrimethylsilane (TMSI) or trimethylsilyl triflate (TMSOTf)yields a nucleoside of cis-configuration of formula (VII). Thisnucleoside is substantially free of the corresponding trans-isomer.

Step 7: The optically active cis-nucleoside of formula (VII) is reducedstereospecifically with a reducing agent preferably lithiumtriethylborohydride or more preferably lithium aluminum hydride in anappropriate solvent such as tetrahydrofuran or diethyl ether to give thecompound of formula (I) and menthol.

Alternatively, as shown in Scheme 3B, the mixture of diastereomers offormula (XIII) is chemoselectively reduced with a suitable reducingagent, such as disiamylborane to give a mixture of four diastereomers offormula (XIV). The hydroxyl groups in this mixture of four diastereomersof formula (XIV) are converted to leaving groups any method in the artto afford a mixture of four diastereomers of formula (VI). Either a cis-or a trans-isomer of formula (VI) is separated out of the mixture offour diastereomers of formula (VI) by fractional crystallization orchromatography. The solvent may be adjusted to select for a cis- ortrans-isomer. The single diastereomer of formula (VI) is reacted withpreviously silylated (or silylated in situ) purine or pyrimidine base oranalogue or derivative. Then, addition of a Lewis acid of formula (III),such as iodotrimethylsilane (TMSI) or trimethylsilyl triflate (TMSOTf)affords a nucleoside of cis- configuration of formula (VII) which isreduced with an appropriate reducing agent to give a specificstereoisomer of formula (I).

Schemes 4A and 4B illustrate the application of the process of Scheme 3to the synthesis of the enantiomers ofcis-2-hydroxymethyl-5-(cytosin-1'-yl)-1,3-oxathiolanes. Although thisprocess is illustrated using specific reagents and starting materials,it will be appreciated by one of skill in the art that suitableanalogous reactants and starting materials may be used to prepareanalogous compounds. ##STR15##

The various steps involved in the synthesis of the nucleosides offormula (I) as depicted in Scheme 4 may be briefly described as follows:

Step 1: The known mercaptoacetic acid of formula (XV) is reacted with anappropriate aldehyde of formula R₃ CHO, wherein R₃ is preferably analkoxy carbonyl, such as menthyl glyoxylate and more preferably acarboxyl group, such as glyoxylic acid (see e.g., J. M. Mcintosh et al.,"2-Mercaptoaldehyde Dimers and 2,5-Dihydrothiophenes from1,3-oxathiolan-5-ones", Can. J. Chem., 61, pp. 1872-1875 (1983)) in acompatible organic solvent, such as toluene, to give the intermediate offormula (XVI).

Step 2: The compound of formula (XVI) is reacted with an appropriatechiral auxiliary, preferably 1-menthol or d-menthol in a compatibleorganic solvent, such as dichloromethane, using an activating agent,such as dicyclohexylcarbodiimide, and an esterification catalyst, suchas 4-dimethylaminopyridine, to give the compounds of formula (XVII).

Step 3: The diastereomeric compounds of formula (XVII) are preferablyseparated by fractional crystallization (Scheme 4A), but may be carriedon further without separation (Scheme4B).

Step 4: The compounds of formula (XVII) are reduced with an appropriatereducing agent such as disiamylborane in a compatible organic solvent,such as tetrahydrofuran (A. Pelter et al., "Borane Reagents", AcademicPress, p. 426 (1988)), to give the compounds of formula (XVIII).

Step 5: The compounds of formula (XVIII) are reacted with an acidchloride or acid anhydride, such as acetic anhydride, in the presence ofpyridine and an acylation catalyst, such as 4-dimethylaminopyridine, togive the compounds of formula (X).

Step 6: The diastereomeric compounds of formula (X), if not alreadyseparated (Scheme 4A), are now separated preferably by fractionalcrystallization (Scheme 4B) to give either the cis- or the trans-acetoxycompound of formula (X).

Step 7: Either the cis- or the trans-acetoxy compound of formula (X) isreacted with cytosine or other purine or pyrimidine base or analoguethereof. The purine or pyrimidine base or analogue is preferablypreviously silylated with hexamethyldisilazane or more preferablysilylated in situ with t-butyldimethylsilyl triflate in a compatibleorganic solvent, such as dichloromethane containing a hindered basepreferably 2,4,6-collidine. A Lewis acid, preferably one derived fromthe compounds of formula (III), more preferably iodotrimethylsilane ortrimethylsilyl triflate, is then added to give the cis compound offormula (XI) in a highly diastereoselective manner.

Step 8: The optically active cis-nucleoside of formula (XI) is reducedstereospecifically with a reducing agent, preferably lithiumtriethylborohydride, or more preferably, lithium aluminum hydride, in anappropriate solvent, such as tetrahydrofuran or diethyl ether, to givethe compound of formula (XII).

In the diastereoselective processes of this invention, the followingintermediates are of particular importance: ##STR16## wherein R₃, R₄ andL are as defined above;

trans-5-hydroxyoxathiolane-2-carboxylic acid;

(1'R,2'S,5'R)-menthyl-1,3-oxathiolan-5-one-2S-carboxylate;

(1'R,2'S,5'R)-menthyl-1,3-oxathiolan-5-one-2R-carboxylate;

(1'R,2'S,5'R)-menthyl-5S-hydroxy-1,3-oxathiolane-2S-carboxylate;

(1'R,2'S,5'R)-menthyl-5R-hydroxy-1,3-oxathiolane-2R-carboxylate;

(1'R,2'S,5'R)-menthyl-5S-hydroxy-1,3-oxathiolane-2R-carboxylate;

(1'R,2'S,5'R)-menthyl-5R-hydroxy-1,3-oxathiolane-2S-carboxylate;

(1'R,2'S,5'R)-menthyl-5S-acetoxy-1,3-oxathiolane-2S-carboxylate;

(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate; (1'R,2'S,5'R)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate;

(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2S-carboxylate;

(1'S,2'R,5'S)-menthyl-5R-acetoxy-1,3-oxathiolane-2S-carboxylate;

(1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate;

(1'S,2'R,5'S)-menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate;

(1,S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolane-2S-carboxylate;

(1,R,2'S,5'R)-menthyl-5S-(cytosin-1"-yl)-1,3-oxathiolane-2R-carboxylate;

(1,S,2'R,5'S)-menthyl-5S-(cytosin-1"-yl)-1,3-oxathiolane-2R-carboxylate;

(1,R,2'S,5'R)-menthyl-5R-(cytosin-1"-yl)-1,3-oxathiolane-2S-carboxylate;

(1,S,2'R,5'S)-menthyl-5R-(cytosin-1"-yl)-1,3-oxathiolane-2S-carboxylate;

(1,R,2,S,5,R)-menthyl-5R-(5"-fluorocytosin-1"-yl)-1,3-oxathiolane-2S-carboxylate;

(1,S,2,R,5'S)-menthyl-5S-(5"-fluorocytosin-1"-yl)-1,3-oxathlolane-2R-carboxylate;(1,S,2,R,5'S)-menthyl-5S-(N-4"-acetylcytosin-1"-yl)-1,3-oxathiolane-2R-carboxylate;

(1,R,2,S,5'R)-menthyl-5S-(cytosin-1"-yl)-1,3-oxathiolane-2R-carboxylate;

(1,S,2,R,5'S)-menthyl-1,3-oxathiolane-2R-carboxylate;

(1,S,2,R,5'S)-menthyl-4R-hydroxy-1,3-oxathiolane-2R-carboxylate and(1'S,2'R,5'S)-menthyl-4S-hydroxy-1,3-oxathiolane-2R-carboxylate;

(1,S,2,R,5'S)-menthyl-4R-chloro-1,3-oxathiolane-2R-carboxylate and(1'S,2'R,5'S)-menthyl-4S-chloro-1,3-oxathiolane-2R-carboxylate;

cis-2(N-methyl-N-methoxyaminocarbonyl)-5-(uracil-1'-yl)-1,3-oxathiolane;

cis- and trans-2-benzoyl-5-acetoxy-1,3-oxathiolane;

cis-2-(1'-pyrrolidinocarbonyl)-5-acetoxy-1,3-oxathiolane;

cis-2-carbomethoxy-5-(5'-bromouracil-1'-yl)-1,3-oxathiolane;

cis-2-carboxyl-5-(uracil-1'-yl)-1,3-oxathiolane;

cis-2-(1'-pyrrolidinocarbonyl)-5-(uracil-1'-yl)-1,3-oxathiolane;

cis-2-benzoyl-5-(uracil-1'-yl)-1,3-oxathiolane;

cis- and trans-isopropyl-5-acetoxy-1,3-oxathiolane-2-carboxylate;

cis-isopropyl-5-(cytosin-1'-yl)-1,3-oxathiolane-2-carboxylate;

cis- and trans-t-butyl-5-acetoxy-1,3-oxathiolane-2-carboxylate;

cis-t-butyl-5-(cytosin-1'-yl)-1,3-oxathiolane-2-carboxylate;

cis- and trans-2-N,N-diethylaminocarbonyl-5-acetoxy-1,3-oxathiolane;

cis-2-N,N-diethylaminocarbonyl-5-(cytosin-1'-yl)-1,3-oxathiolane;

cis- and trans-2-carboethoxy-4-acetoxy-1,3-dioxolane;

cis- and trans-2-carboethoxy-4-(thymin-1'-yl)-1,3-dioxolane; and

cis- and trans-2-carboethoxy-4-(N-4'-acetylcytosin-1'-yl)-1,3-dioxolane.

The following examples illustrate the present invention in a manner ofwhich it can be practiced but, as such, should not be construed aslimitations upon the overall scope of the processes of this invention.Except where specifically noted, all [α]_(D) measurements were recordedat ambient temperature.

EXAMPLE 1

1,3-OXATHIOLAN-5-ONE-2-CARBOXYLIC ACID ##STR17##

Toluene (700 mL), mercaptoacetic acid (38 mL, 50.03 g, 0.543 mol), andp-toluenesulfonic acid (1.0 g) were added to a solution of glyoxylicacid monohydrate (50.0 g, 0.543 mol) in 200 mL of THF in a 2 L roundbottom flask equipped with a Dean-Stark trap and condenser. Theresultant reaction mixture was refluxed for 3 hours until 24.0 mL of H₂O was azeotropically removed. The reaction mixture was cooled, followedby removal of solvent under reduced pressure to yield an off-whitesolid. This material was purified by recrystallization (hexanes-EtOAc)to give 60.0 g of the product as a crystalline white solid: m.p.140°-143° C.; ¹ H NMR (DMSO) δ3.84 (g, 2H, JAB=16.7 Hz), 6.00 (s, 1H).

EXAMPLE 2

TRANS-5-HYDROXYOXATHIOLANE-2-CARBOXYLIC ACID ##STR18##

A suspension of dithian-1,4-diol (82.70 g, 0.54 mol) and glyoxylic acidmonohydrate (100.0 g, 1.09 mol) in tert-butyl methyl ether (1.1 L) wasstirred under a blanket of nitrogen and heated to reflux under Dean andStark conditions. The reflux was continued for 8 hours during which time15.3 mL (0.85 mol) of water was collected. The slightly turbid mixturewas filtered, and the solvent was distilled at atmospheric pressureuntil a volume of 600 mL remained. Cyclohexane (340 mL) was added andthe solution was cooled to 5° C., seeded, and allowed to stir andcrystallize. The suspension was stirred at 0°-5° C. for 2 hours. Theproduct was isolated by filtration, washed with 100 mL of tert-butylmethyl ether-cyclohexane (2:1), and was dried overnight in vacuo at roomtemperature (94.44 g): m.p. 94.5° C.; ¹ HNMR (DMSO) δ2.85 (dd, 1H,J=2.4, 10.5 Hz), 3.13 (dd, 1H, J=4.3, 10.5 Hz), 5.47 (s, 1H), 5.84 (brs,1H), 6.95 (d, 1H, J=4.7 Hz).

EXAMPLE 3

TRANS-5-ACETOXY-1,3-OXATHIOLANE-2-CARBOXYLIC-ACID ##STR19##

One drop of concentrated H₂ SO₄ was added to a thoroughly stirredsolution of trans-5-hydroxyoxathiolane-2-carboxylic acid (7.0 g, 46.7mmol) in glacial acetic acid (40 mL) and acetic anhydride (15 mL, 15.9mmol) at ambient temperature. The resultant clear solution was stirredfor I hour and then poured onto crushed ice and brine (20 mL). Thismixture was extracted with CH₂ Cl₂ (100 mL) and the combined extract wasdried over anhydrous magnesium sulfate. The solvent was removed underreduced pressure to give 8.5 g (95%) of a light yellow syrup whichconsisted of trans- and cis-5-acetoxy-1,3-oxathiolane-2-carboxylic acidin a 2:1 ratio. The mixture was dissolved in benzene (20 mL) and wasleft standing overnight during which white crystals were formed. A smallamount of ether was added and the solid was collected by filtration andwashed with more ether to give 2 g (22%) oftrans-5-acetoxy-1,3-oxathiolane-2-carboxylic acid: m.p. 111.3° C.; ¹ HNMR (DMSO) δ2.03 (s, 3H), 3.21 (d, 1H, J=12 Hz), 3.32 (dd, 1H, J=3, 12Hz), 5.65 (s, 1H), 6.65 (d, 1H, J=4 Hz); ¹³ C NMR (DMSO) δ20.91, 36.51,78.86, 99.15, 169.36, 170.04.

EXAMPLE 4

CIS-5-ACETOXY-1,3-OXATHIOLANE-2-CARBOXYLIC ACID ##STR20##

The filtrate obtained from Example 3 was concentrated under reducedpressure and redissolved in ether. This solution was kept at roomtemperature and cis-5-acetoxy-1,3-oxathiolane-2-carboxylic acid slowlycrystallized out as a white solid (2.1 g, 23%): m.p. 111.7° C.; ¹ H NMR(DMSO) δ1.96 (s, 3H), 3.25-3.33 (m, 2H), 5.74 (S, 1H), 6.69 (d, 1H, J=3Hz); ¹³ C NMR (DMSO) δ21.0, 37.16, 79.57, 98.58, 169.36, 170.69.

EXAMPLE 5

(1,R,2,S,5,R)-MENTHYL-1,3-OXATHIOLAN-5-ONE-2S-CARBOXYLATE AND(1'R,2'S,5'R)-MENTHYL-1,3-OXATHIOLAN-5-ONE-2R-CARBOXYLATE ##STR21##

Oxalyl chloride (11 mL, 123.6 mmol) was added through a dropping funnelover a period of 30 minutes to a stirred solution of1,3-oxathiolan-5-one-2-carboxylic acid (12.2 g, 82.4 mmol) in anhydrousTHF (20 ml) and CH₂ Cl₂ (40mL) at room temperature under an argonatmosphere. The resultant solution was heated at 65° C. for 30 minutesand then was concentrated in vacuo to give an oily product (11.6 g,90%). The crude acid chloride obtained was redissolved in dry CH₂ Cl₂(40 mL) and cooled at 0° C. (1R,2S,5R)-menthol (12.8 g, 82.4 mmol)dissolved in CH₂ Cl₂ (25 mL) was slowly added to this cooled solution.The resultant solution was stirred at room temperature overnight. Thereaction mixture was diluted with CH₂ Cl₂ (200 mL) and washed withwater, saturated aqueous NaHCO₃ solution, brine, and then was dried overanhydrous Na₂ SO₄. The solvent was removed and the crude product thusobtained was filtered through a short silica column (100 g, Merck)eluted with EtOAc-hexanes. Concentration of the appropriate fractionsgave a 1:1 mixture of(1'R,2'S,5'R)-menthyl-1,3-oxathiolan-5-one-2S-carboxylate and(1,R,2'S,5'R)-menthyl-1,3-oxathiolan-5-one-2R-carboxylate (20 g, 84.7%overall) as a viscous oil: ¹ H NMR (CDCl₃) δ0.77 (3H), 0.91 (6H),1.00-1.15 (2H), 1.40-2.10 (6H), 3.56 (1H), 3.82 (1H), 4.80 (1H). 5.62(1H); ¹³ C NMR δ16.7, 21.2, 21.3, 22.5, 23.80, 23.84, 26.7, 26.8, 30.6,31.91, 31.94, 34.57, 40.6, 41.07, 47.5, 47.6, 74.1, 74.2, 77.7, 168.1,172.8.

The above mixture (20 g) was dissolved in a minimum amount ofpentans-petroleum ether (40°-60° C.) (1:2, 30 mL). The resultantsolution was cooled at -70° C. for 10 minutes and the crystallinecompound that was formed was quickly collected by filtration and washedwith more cold petroleum ether (10 mL). This crystalline compound,isolated in 12.5% yield, was found to consist of one isomer as indicatedby ¹ HNMR and ¹³ C NMR spectroscopy: m.p. 78.5°; [α]_(D) +31.7° (c,0.984, CHCl₃); ¹ H NMR (CDCl₃) δ0.77 (3H), 0.91 (6H), 1.00-1.15 (2H),1.40-2.10 (6H), 3.56 (1H), 3.82 (1H), 4.79 (1H), 5.62 (1H); ¹³ C NMR(CDCl₃) δ16.7, 21.2, 22.5, 23.8, 26.7, 30.0, 32.0, 34.6, 41.1, 47.6,77.7, 168.1, 172.9.

EXAMPLE 6

(1'R,2'S,5'R)-MENTHYL-5S-HYDROXY-1,3-OXATHIOLANE-2S-CARBOXYLATE,(1'R,2'S,5'R)-MENTHYL-5R-HYDROXY-1,3-OXATHIOLANE-2R-CARBOXYLATE,(1'R,2'S,5'R)-MENTHYL-5S-HYDROXY-1,3-OXATHIOLANE-2R-CARBOXYLATE,(1'R,2'S,5'R)-MENTHYL-5R-HYDROXY-1,3-OXATHIOLANE-2S-CARBOXYLATE##STR22##

A freshly prepared solution of disiamylborane (13.4 mmol, 0.5M in THF)was added via canula to a stirred solution of a 1:1 mixture of thementhyl ester carboxylate of formula (XVII) (1.28 g, 4.47 mmol) in THF(10 mL) at 0° C. under an argon atmosphere. The resulting clear solutionwas stirred for 15 minutes at 0° C. and 18 hours at ambient temperature.The reaction was quenched with methanol (5 mL), concentrated, anddiluted with methylene chloride (20 mL). The resultant solution waswashed with brine (5×2 mL) and dried over anhydrous magnesium sulfate.Removal of the solvent gave a clear oil. Subjecting this material tosilica gel column chromatography (EtOAc-hexanes, 1:2, V/V) gave 0.65 g(50%) of the expected lactols in four diastereomeric forms: ¹ H NMR(CDCl₃) δ0.71-2.09 (m, 18H), 3.01-3.09 (m, 1H), 3.24-3.33 (m, 1H),4.66-4.83 (m, 1H), 5.53-5.59 (m, 1H), 5.88-6.09 (m, 1H).

EXAMPLE 7

(1'R,2'S,5'R)-MENTHYL-5S-ACETOXY-1,3-OXATHIOLANE-2S-CARBOXYLATE,(1'R,2'S,5'R)-MENTHYL-5R-ACETOXY-1,3-OXATHIOLANE-2R-CARBOXYLATE,(1'R,2'S,5'R)-MENTHYL-5S-ACETOXY-1,3-OXATHIOLANE-2R-CARBOXYLATE, (1'R,2'S,5'R)-MENTHYL-5R-ACETOXY-1,3-OXATHIOLANE-2S-CARBOXYLATE ##STR23##

The four title compounds were prepared as a mixture by the following twomethods.

Method A

Lactols of formula (XVIII) (0.65 g, 2.25 mmol) were dissolved inanhydrous pyridine (1.5 mL) and methylene chloride (5 mL). Acetylchloride (0.5 mL, 7.0 mmol) was slowly added to this solution at 0° C.The resulting white suspension was stirred at ambient temperature for 3hours. The reaction was then quenched with saturated aqueous ammoniumchloride solution (1 mL). The mixture was extracted with methylenechloride (5×2 mL) and the combined extract was concentrated to give abrown gummy material. This material was subjected to columnchromatography (EtOAc-hexane, 1:3 V/V) to provide 0.3 g of the fouracetates as a light yellow oil: ¹ H NMR (CDCl₃) δ0.75 (d, 6H, J=7 Hz),0.78 (d, 6H, J=7 Hz), 0.88-0.94 (m, 24H), 0.97-2.03 (m, 36M), 2.10 (s,9H), 2.13 (s, 3H), 3.15 (d, 2H, J=12 Hz), 3.23-3.30 (m, 4H), 3.42 (dd,1H, J=4, 12 Hz), 3.44 (dd, 1H, J=4, 12 Hz), 4.65-4.75 (m, 4H), 5.61 (s,1H), 5.62 (s, 1H), 5.63 (s, 1H), 5.64 (s, 1H), 6.64 (m, 4H).

Method B

A solution of dicyclohexyl-carbodiimide (21.86 g, 0.106 mol) indichloromethane (100 mL) was added to a 500 mL round bottom flaskcontaining a solution of trans- andcis-5-acetoxy-1,3-oxathiolane-2-carboxylic acid (X) (18.5 g, 0.096 mol),(1R,2S,5R)-(-)-menthol (16.5 g, 0.106 mol), and 4-dimethyl-aminopyridine(1.17 g, 9.63 mmol) in dichloromethane (200 mL) at 0° C. The resultingthick white slurry was stirred at room temperature for 3 hours at whichtime methanol (4.0 mL) and glacial acetic acid (2.0 mL) were added.After stirring for 10 minutes, the reaction mixture was diluted withhexanes (200 mL) and filtered through Celite. Subsequent removal of thesolvent provided 32.5 g of the crude product. This substance wasredissolved in hexanes (100 mL), filtered through Celite andconcentrated to yield 30.5 g of material which was further purified bycolumn chromatography (eluent: 100% hexanes to 5% EtOAc-hexanes) to give5.5 g of a mixture (ca. 1:1) of(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2S-carboxylate and(1,R,2,S,5'R)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate; 10.28 gof a material which contained mainly the above two diastereomers alongwith (1,R,2,S,5,R)-menthyl-5S-acetoxy-1,3-oxathiolane-2S-carboxylate and(1,R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate; 7.6 gof a random mixture of the above four diastereomers; and 2.2 g of amixture (ca. 1:1) of(1'R,2'S,5'R)-menthyl-5S-acetoxy-1,3-oxathiolane-2S-carboxylate and(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate.

EXAMPLE 8

(1'R,2,S,5,R)-MENTHYL-5R-ACETOXY-1,3-OXATHIOLANE-2R-CARBOXYLATE##STR24##

(1'R,2'S,5'R)-Menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate wasprepared by the following three methods.

Method A

A mixture of(1'R,2'S,5'R)-menthyl-5S-acetoxy-1,3-oxathiolane-2S-carboxylate and(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate (5.5 g)obtained from Example 7 was dissolved in petroleum ether (40°-60° C.)containing a minimum amount of diethyl ether and cooled in a dryice-acetone bath. The white solid precipitate was immediately collectedby suction filtration to give 1.6 g of(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate: m.p.105.2° C.; [α]_(D) -60° (c, 0.51, CHCl₃); ¹ H NMR (CDCl₃) δ0.77 (d, 3H,J=7 Hz), 0.91 (d, 3H, J=7 Hz), 0.92 (d, 3H, J=7 Hz), 0.86-2.06 (m, 9H),2.10 (s, 3H), 3.16 (d, 1H, J=12 Hz), 3.44 (dd, 1H, J=4, 12 Hz), 4.74(dt, 1H, J=5, 12 Hz), 5.63 (s, 1H), 6.79 (d, 1H, J=4 Hz); ¹³ C NMR(CDCl₃) δ16.16, 20.74, 21.11, 21.97, 23.29, 26.08, 31.38, 34.13, 37.24,40.62, 47.07, 76.11, 79.97, 99.78, 168.60, 169.68.

Method B

A mixture of the four diastereomers of formula (X) (300 mg) wasdissolved in n-pentane containing a minimum amount of diethyl ether andwas kept at -20° C. for 24 hours. The white needles formed were filteredquickly while cold to give 25 mg of material. The substance thusisolated was found to be identical in all respects with those obtainedby Method A or C.

Method C

A solution of dicyclohexylcarbodiimide (1.362 g, 6.6 mmol) indichloromethane (5 mL) was added to a 50 mL round bottom flaskcontaining a solution of trans-5-acetoxy-1,3-oxathiolane-2-carboxylicacid (1.16 g, 6.04 mmol), (1R,2S,5R)-(-)-menthol (1.038 g, 6.60 mmol),and 4-dimethylaminopyridine (75 mg, 0.62 mmol) in dichloromethane (10mL) at 0° C. The resulting white slurry was stirred at room temperaturefor 3 hours at which time methanol (0.2 mL) and glacial acetic acid (0.2mL) were added. After stirring for 10 minutes, the reaction mixture wasdiluted with hexanes (25 ml), filtered through Celite, and concentrated.The crude product thus obtained was dissolved in hexanes (25 mL),filtered through Celite and concentrated to provide 1.98 g (100%) of(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate and(1'R,2'S,5'R)-menthyl-5S-acetoxy-1,3-oxathiolane-2S-carboxylate: ¹ H NMR(CDCl₃) δ0.75 (d, 3H, J=7 Hz), 0.78 (d, 3H, J=7 Hz), 0.85-0.92 (m, 12H),0.95-2.19 (m, 18H), 2.10 (s, 6H), 3.15 (d, 2H, J=12 Hz), 3.42 (dd, 1H,J=4, 12 Hz), 3.44 (dd, 1H, J=4, 12 Hz),4.74 (dt, 2H, J=5, 12 Hz), 5.61(s, 1H), 5.62 (s, 1H), 6.65 (s, 2H)

The above mixture of diastereoisomers was dissolved in petroleum ether(40°-60° C.) containing a minimum amount of diethyl ether and was cooledin a dry ice-acetone bath. The white solid precipitate was immediatelycollected (620 mg) by suction filtration. This material wasrecrystallized again under the same conditions to yield 450 mg of awhite solid. This compound was found to be identical in all respects tothose prepared using either method A or method B.

EXAMPLE 9

(1'S,2'R,5'S)-MENTHYL-5S-ACETOXY-1,3-OXATHIOLANE-2S-CARBOXYLATE##STR25##

A solution of dicyclohexylcarbodiimide (491 mg, 2.38 mmol) indichloromethane (7 mL) was added to a 50 mL round bottom flaskcontaining a solution of trans-5-acetoxy-1,3-oxathiolane-2-carboxylicacid (IX) (416 mg, 2.2 mmol), (1S,2R,5S)-(+)-menthol (372 mg, 2.38mmol), and 4-dimethylamino-pyridine (26 mg, 0.21 mmol) indichloromethane (5 mL) at 0° C. The resulting thick slurry was stirredat room temperature for 3 hours at which time methanol (0.2 mL) andglacial acetic acid (0.2 mL) were added. After stirring for 10 minutes,the mixture was diluted with hexanes (25 mL), filtered through Celite,and concentrated. The crude product obtained was dissolved in hexanes(25 mL), filtered through Celite, and concentrated to produce 0.715 mg(100%) of two diastereomers, namely(1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolane-2S-carboxylate and(1'S,2'R,5'S)-menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate: ¹ H NMR(CDCl₃) δ0.75 (d, 6H, J=7 Hz), 0.85-0.92 (m, 12H), 0.95-2.19 (m, 18H),2.10 (s, 6H), 3.15 (d, 2H, J=12 Hz), 3.42 (dd, 1H, J=4, 12 Hz), 3.44(dd, 1H, J=4, 12 Hz), 4.72 (dr, 2H, J=5, 12 Hz) 5.61 (S, 1H), 5.62 (S,1H), 6.65 (S, 2H).

The above diastereomeric acetoxy menthyl esters mixture was dissolved inpetroleum ether (40°-60° C.) containing a minimum amount of diethylether and was cooled in a dry ice-acetone bath. The white solidprecipitate was immediately collected (200 mg) by suction filtration.This material was recrystallized again under the same conditions toyield 130 mg (34% based on one enantiomer) of(1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolane-2S-carboxylate: m.p.104.2° C.; [α]_(D) +59.2° (c, 1.02, CHCl₃); ¹ H NMR (CDCl₃) δ0.77 (d,3H, J=7 Hz), 0.91 (d, 3H, J=7 Hz), 0.92 (d, 3H, J=7 Hz), 0.86-2.06 (m,9H), 2.10 (s, 3H), 3.16 (d, 1H, J=12 Hz), 3.44 (dd, 1H,J=4, 12 Hz), 4.74(dt, 1H, J=5, 12 Hz), 5.63 (s, 1H), 6.79 (d, 1H., J=4 Hz); ¹³ C NMR(CDCl₃) δ16.16, 20.74, 21.11, 21.97, 23.29, 26.08, 31.38, 34.13, 37.24,40.62, 47.07, 76.11, 79.96, 99.78, 168.60, 169.68.

EXAMPLE 10

(1'R,2'S,5'R)-MENTHYL-5R-ACETOXY-1,3-OXATHIOLANE-2S-CARBOXYLATE##STR26##

(1'R,2'S,5'R)-Methyl-5R-acetoxy-1,3-oxathiolane-2S-carboxylate wasprepared by the following two methods.

Method A

A saturated solution of a mixture of the four diastereomers (12.28 g),obtained in Example 7, was prepared in petroleum ether containing aminimum amount of diethyl ether and was kept at -20° C. for 72 hours.The white crystalline solid produced was isolated by filtration to give1.6 g of(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2S-carboxylate: m.p.110.2° C.; [α]_(D) -177° (c, 0.7, CHCl₃); ¹ H NMR (CDCl₃) δ0.75 (d, 3H,J=7 Hz), 0.88 (d, 3H, J=7 Hz), 0.92 (d, 3H, J=7 Hz), 0.97-2.02 (m, 9H),2.12 (s, 3H), 3.22 (d, 1H, J=11 Hz), 3.29 (dd, 1H J=4, 11 Hz), 4.74 (dt,1H, J=4, 11 Hz), 5.63 (s, 1H), 6.65 (d, 1H, J=3 Hz); ¹³ C NMR (CDCl₃)δ16.9, 20.69, 21.19, 21.95, 23.29, 26.10, 31.34, 34.0, 37.62, 40.32,46.82, 75.69, 80.20, 99.36, 168.55, 170.23.

Method B

A solution of dicyclohexylcarbodiimide (118 mg, 0.572 mmol) indichloromethane (5 mL) was added to a 25 mL round bottom flaskcontaining a solution of cis-5-acetoxy-1,3-oxathiolane-2-carboxylic acid(100 mg, 0.52 mmol), (1R,2S,5R)-(-)-menthol (85 mg, 0.54 mmol), and4-dimethyl-aminopyridine (DMAP) (8 mg, 0.053 mmol) in dichloromethane(10 ml) at 0° C. The resulting white slurry was stirred at roomtemperature for 3 hours at which time methanol (0.1 mL) and glacialacetic acid (0.1 mL) was added. After stirring for 10 minutes, themixture was diluted with hexanes (15 mL), filtered through Celite, andconcentrated. The crude product obtained was dissolved in hexanes (15mL), filtered through Celite, and concentrated to yield 170 mg (100%) of(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2S-carboxylate and(1'R,2'S,5'R)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate: ¹ H NMR(CDCl₃) δ0.75 (d, 3H, J=7 Hz), 0.78 (d, 3H, J=7 Hz), 0.88-0.94 (m, 12H),0.97-2.03 (m, 18H), 2.10 (s, 3H), 2.13 (s, 3H), 3.23-3.30 (m, 4H),4.65-4.75 (m, 2H), 5.63 (s, 1H), 5.64 (s, 1H), 6.64 (m, 2H).

The above mixture of diastereomers was recrystallized from petroleumether (40°-60° C.) and a minimum amount of diethyl ether at roomtemperature. The white crystalline material formed was collected (95 mg)by filtration. This material was recrystallized again from diethylether-petroleum ether to yield 74 mg (78% based on one enantiomer) of(1'R,2'S,5'R) menthyl-5R-acetoxy-1,3-oxathiolane-2S-carboxylate.

EXAMPLE 11

(1'S,2'R,5'S)-MENTHYL-5S-ACETOXY-1,3-OXATHIOLANE-2R-CARBOXYLATE##STR27##

A solution of dicyclohexylcarbodiimide (1.588 g, 7.7 mmol) indichloromethane (7 mL) was added to a 50 ml round bottom flaskcontaining a solution cis-5-acetoxy-1,3-oxathiolane-2-carboxylic acid(1.36 g, 7 mmol), (1S,2R,5S)-(+)-menthol (1.216 g, 7.7 mmol), and4-dimethylamino-pyridine (85 mg, 0.7 mmol) in dichloromethane (16 mL) at0° C. The resulting thick slurry was stirred at room temperature for 3hours. The reaction was quenched with methanol (0.4 mL) and glacialacetic acid (0.4 mL) and the mixture was stirred for 10 min. Theresultant mixture was diluted with hexanes (25 mL), filtered through apad of Celite, and concentrated. The crude material thus obtained wasredissolved in hexanes (25 mL) and filtered through Celite. Removal ofthe solvent under reduced pressure yielded 2.3 g of a white solid (100%)which consisted of(1,S,2,R,5,S)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate and(1,S,2'R,5'S)-menthyl-5R-acetoxy-1,3-oxathiolane-2S-carboxylate:

¹ H NMR (CDCl₃) δ0.75 (d, 3H, J=7 Hz), 0.78 (d, 3H, J=7 Hz), 0.88-0.94(m, 12H), 0.97-2.03 (m, 18H), 2.10 (s, 3H), 2.13 (s, 3H), 3.23-3.30 (m,4H), 4.65-4.74 (m, 2H), 5.63 (s, 1H), 5.64 (s, 1H), 6.64 (m, 2H).

The above mixture of diastereomers was recrystallized from petroleumether (40°-60° C.) and a small amount of diethyl ether at roomtemperature to give 1.3 g of a white solid. This material wasrecrystallized again from diethyl ether-petroleum ether (40°-60° C.) togive 900 mg (78% based on one enantiomer) of(1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate: m.p.110.2° C.; [α]_(D) +177° (C, 1.0, CHCl₃); ¹ H NMR (CDCl₃) δ0.75 (d, 3H,J=7 Hz), 0.89 (d, 3H, J=7Hz), 0.92 (d, 3H, J=7 Hz), 0.98-2.02 (m, 9H),2.12 (s, 3H), 3.22 (d, 1H, J=11 Hz), 3.29 (dd, 1H, J=4, 11 Hz), 4.74(dt, 1H, J=11, 4 Hz), 5.63 (s, 1H), 6.65 (d, 1H, J=3 Hz); ¹³ C NMR(CDCl₃) δ16.9, 20.69, 21.19, 21.95, 23.29, 26.10, 31.34, 34.09, 37.62,40.32, 46.82, 75.79, 80.20, 99.36, 168.55, 170.23.

EXAMPLE 12

(1'R,2'S,5'R)-MENTHYL-5S-(CYTOSIN-1"-YL)-1,3-OXATHIOLANE-2R-CARBOXYLATE##STR28##

t-Butyl-dimethylsilyl trifluoromethanesulfonate (1.1 mL, 4.79 mmol) wasadded to a suspension of cytosine (0.27 g, 2.5 mmol) in CH₂ Cl₂ (2 mL)containing 2,4,6-collidine (0.65 ml, 4.92 mmol) at room temperature. Theresultant mixture was stirred for 15 minutes and a clear solution wasproduced. A solution of(1'R,2'S,5'R)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate (0.66 g,1.99 mmol) in methylene chloride (1.5 mL) was added to the mixture andstirring was continued for 5 minutes. Iodotrimethylsilane (0.31 mL, 2.18mmol) was introduced dropwise and a white precipitate was produced whenthe addition was completed. The reaction mixture was allowed to stir for18 hours. The reaction was quenched by addition of a saturated aqueoussolution of Na₂ S₂ O₃ (10 mL) and CH₂ Cl₂ (30 mL). The organic layer wasseparated and washed with brine (2×10 mL). The solvent was removed invacuo to give a viscous oil which was suspended in diethyl ether (30mL). To this suspension was added a saturated aqueous solution of NaHCO₃(20 mL) with vigorous stirring. A white precipitate appeared and theresultant suspension was diluted with hexanes (10 mL). The precipitatewas collected by filtration to give 0.57 g (75%) of a white solid. The ¹H NMR spectrum of this material indicated that it was a mixture of thecis- and trans- diastereomers of the expected nucleoside in a 23:1ratio.

This product was purified further by recrystallization fromEtOAc-hexanes-MeOH: [α]_(D) -144° (c, 1.02, CHCl₃); m.p. 219° C.(decomposed); ¹ H NMR (CDCl₃) δ0.76 (d, 3H, J=7 Hz), 0.85-0.94 (m, 6H),1.02-1.10 (m, 2H), 1.42-2.06 (m, 7H), 3.14 (dd, 1H, J=6.6, 12.1 Hz),3.54 (dd, 1H, J=4.7, 12.1 Hz), 4.72-4.78 (m, 1H), 5.46 (s, 1H), 5.99 (d,1H, J=7.5 Hz), 8.43 (d, 1H, J=7.6 Hz); ¹³ C (CDCl₃) δ16.1, 20.7, 21.9,23.2, 26.4, 31.4, 34.0, 36.3, 40.7, 47.1, 76.7, 78.4, 90.3, 94.6, 141.8,155.4, 165.6, 169.8.

EXAMPLE 13

(1'S,2'R,5'S)-MENTHYL-5S-(CYTOSIN-1"-YL)-1,3-OXATHIOLANE-2R-CARBOXYLATE##STR29##

2,4,6-Collidine (0,317 mL, 2.4 mmol) and t-butyldimethylsilyltrifluoromethanesulfonate (0.551 mL, 2.4 mmol) were added successivelyto a suspension of cytosine (133.3 mg, 1.2 mmol) in CH₂ Cl₂ (1 mL) atroom temperature under an argon atmosphere. The resultant mixture wasstirred for 15 minutes to produce a clear solution. A solution of(1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate (330 mg,1 mmol) in CH₂ Cl₂ (0.5 mL) was introduced, followed byiodotrimethylsilane (0.156 ml, 1.1 mmol). The resultant mixture wasstirred for 3 hours. The mixture was diluted with CH₂ Cl₂ (20 mL) andwashed successively with saturated aqueous NaHSO₃, water, and brine. Thesolvent was evaporated and the residue was taken up in ether-hexanes(1:1, 10 mL) and saturated aqueous NaHCO₃ (2 mL). Stirring was continuedfor 15 minutes. The aqueous layer was removed and the organic phase wascentrifuged to give a white solid which was washed with hexanes (3×5 mL)and dried under vacuum. This substance, namely (1'S,2'R,5'S)-menthyl-5S-(cytosin-1"-yl)-1,3-oxathiolan-2R-carboxylate (380 mg, 100%)was contaminated with about 3% of (1'S,2'R,5'S)-menthyl-5R-(cytosin-1"-1,3-oxathiolan-2R-carboxylate (as indicated byits ¹ H NMR spectrum), was recrystallized from MeOH to give(1'S,2'R,5'S)-menthyl-5S-(cytosin-1"-yl)-1,3-oxathiolane-2R-carboxylate:[α]_(D) -58° (c, 0.506, CHCl₃); m.p.: 235° C. (decomposed)); ¹ H NMR(CDCl₃) δ0.80 (3H), 0.92 (6H), 1.06 (2H), 1.37-2.10 (7H), 3.11 (1H),3.55 (1H), 4.77 (1H), 5.47 (1H), 5.79 (1H), 6.49 (1H), 8.37 (1H); ¹³ CNMR (CDCl₃) δ6.8, 21.3. 22.5, 23.9, 26.8, 32.0, 34.6, 37.0, 40.7, 47.4,77.3, 79.3, 90.9, 95.3, 142.9, 155.1, 164.9, 170.1.

EXAMPLE 14

(1'R,2'S,5'R)-MENTHYL-5R-(CYTOSIN-1"-YL)-1,3-OXATHIOLANE-2S-CARBOXYLATE##STR30##

2,4,6-collidine (0.317 mL, 2.4 mmol) and t-butyldimethylsilyltrifluoromethanesulfonate (0.551 mL, 2.4 mmol) were added successivelyto a suspension of cytosine (133.3 mg, 1.2 mmol) in CH₂ Cl₂ (1 mL) atroom temperature under an argon atmosphere. The resultant mixture wasstirred for 15 minutes and a clear solution was obtained. A solution of(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolan-2S-carboxylate (330 mg,1 mmol) in CH₂ Cl₂ (0.5 mL) was introduced, followed byiodotrimethylsilane (0.156 mL, 1.1 mmol). Stirring was continued for 3hours. The mixture was diluted with CH₂ Cl₂ (20 mL) and washedsuccessively with saturated aqueous NaHSO₃, water, brine and then wasconcentrated. The residue was taken up in ether-hexanes (1:1, 10 mL) andsaturated aqueous NaHCO₃ (2 mL) and was stirred at room temperature for15 minutes. The aqueous layer was removed and the organic phase wascentrifuged to yield a white solid which was washed with hexanes (3×5mL) and then dried under vacuum. The product(1',R,2'S,5'R)-menthyl-5R-(cytosin-1"-yl)-1,3-oxathiolan-2S-carboxylate(336.3 mg, 88%) contained about 6% of(1'R,2'S,5'R)-menthyl-5S-(cytosin-1"-yl)-1,3-oxathiolan-2S-carboxylate(NMR). This material was recrystallized from MeOH to give the desiredproduct: [α]_(D) +56° (c, 1.08, CHCl₃); m.p.: 235° C. (decomposed); ¹ HNMR (CDCl₃) δ0.80 (3H) 0.91 (6H), 1.00 (2H), 1.37-2.10 (7H), 3.11 (1H),3.55 (1H), 4.77 (1H), 5.47 (1H), 5.79 (1H), 6.49 (1H), 8.37 (1H); ¹³ CNMR (CDCl₃) δ16.8, 21.3. 22.5, 23.9, 26.8, 32.0, 34.6, 36.8, 40.7, 47.4,77.1, 78.8, 90.9, 95.6, 141.9, 156.3, 166.6, 170.2.

EXAMPLE 15

(1,S,2,R,5'S)-MENTHYL-5R-(CYTOSIN-1"-YL)-1,3-OXATHIOLANE-2S-CARBOXYLATE##STR31##

2,4,6-collidine (0.106 mL, 0.8 mmol) and t-butyldimethylsilyltrifluoromethanesulfonate were added successively to a suspension ofcytosine (44 mg, 0.4 mmol) in CH₂ Cl₂ (0.5 mL) at room temperature underan argon atmosphere. Stirring was continued at room temperature for 15minutes and a clear solution was produced. A solution of(1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolan-2S-carboxylate (110 mg,0.33 mmol) in CH₂ Cl₂ (0.3 mL) was added, followed byiodotrimethylsilane (0.052 mL, 0.36 mmol). The resultant mixture wasstirred at room temperature overnight and then was diluted with CH₂ Cl₂(10 mL). The mixture was washed successively with saturated aqueousNaHSO₃, water, brine and concentrated under reduced pressure. Theresidue was taken up in ether-hexanes (1:1, 5 mL) and saturated aqueousNaHCO₃ (1 mL) and stirring was continued at room temperature for 20minutes. The aqueous layer was removed and the white solid suspended inthe organic phase was collected by centrifugation. This solid was washedwith hexanes (3×5 mL) and dried under vacuum to provide 65 mg (51.2%) of(1,S,2,R,5'S)-menthyl-5R-(cytosin-1"-yl)-1,3-oxathiolan-2S-carboxylatecontaminated with approximately 5% of(1'S,2'R,5'S)-menthyl-5S-(cytosin-1"-yl)-1,3-oxathiolan-2S-carboxylateas indicated by ¹ H NMR spectroscopy. Recrystallization of the crudematerial from MeOH-Et₂ O gave the desired product: m.p. 210°-211° C.;[α]_(D) +179° (c, 0.66, CHCl₃); ¹ H NMR (CDCl₃) δ0.77 (3H) 0.92 (6H),1.00 (2H), 1.37-2.10 (6H), 3.14 (1H), 3.55 (1H), 4.76 (1H), 5.46 (1H),5.88 (1H), 6.46 (1H), 8.38 (1H); ¹³ C NMR (CDCl₃) δ16.8, 21.3. 21.8,22.5, 23.9, 26.7, 31.9, 34.7, 38.7, 40.9, 47.4, 76.4, 80.8, 100.0,169.1, 170.8

The washings and the supernatant were combined and washed with 1N HCl,water, brine, and then was dried over Na₂ SO₄. Evaporation of thesolvent yielded 53 mg (48%) of unreacted(1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolan-2S-carboxylate.

EXAMPLE 16

2R-HYDROXYMETHYL-5S-(CYTOSIN-1'-YL)-1,3-OXATHIOLANE ##STR32##

A solution of (1'R,2'S,5'R)-menthyl-5S-(cytosin-1"-yl)-1,3-oxathiolane-2R-carboxylate (67 mg, 0.18 mmol) in THF (1 mL) wasslowly added to a stirred suspension of lithium aluminum hydride (19 mg,0.5 mmol) in THF (2 mL) at ambient temperature under an argonatmosphere. Stirring was continued for 30 minutes. The reaction was thenquenched with methanol (3 mL), followed by the addition of silica gel (5g). The resultant slurry was stirred for 30 minutes and then wastransferred to a short column packed with Celite and silica gel and waseluted with a 1:1:1 mixture of EtOAc-hexane-methanol (50 mL). The eluatewas concentrated and subjected to silica gel column chromatography(EtOAc-hexane-methanol, 1:1:1) to give a gummy solid. This solid wasdried azeotropically with toluene to give 38 mg (94%) of the desiredproduct: [α]_(D) -122° (C, 1.01, MeOH); m.p. 128°-130° C.; ¹ H NMR (CD₃OD) δ3.05 (dd, 1H, J=4.3, 11.9 Hz) 3.42 (dd, 1H, J=5.3, 11.9 Hz),3.76-3.89 (m, 2H), 5.19-5.21 (m, 1H), 5.81 (d, 1H, J=7.6 Hz), 6.20-6.23(m, 1H), 7.01-7.16 (brm, 2H, exchangeable), 7.98 (d, 1H, J=7.5 Hz); ¹³ C(CD₃ OD) δ38.5, 64.1, 88.0, 88.9, 95.7, 142.8, 157.9, 167.7.

EXAMPLE 17

2S-HYDROXYMETHYL-5R-(CYTOSIN-1'-YL)-1,3-OXATHIOLANE ##STR33##

A solution of(1'R,2'S,5'R)-menthyl-5R-(cytosin-1"-yl)-1,3-oxathiolane-2S-carboxylate(102 mg, 0.27 mmol) in THF (3 mL) was slowly added to a stirredsuspension of lithium aluminum hydride (20 mg, 0.54 mmol) in THF (2 mL)at ambient temperature under an argon atmosphere. Stirring was continuedfor 30 minutes and the reaction was quenched with methanol (5 mL),followed by the addition of silica gel (7 g). The resultant slurry wasstirred for 30 minutes, transferred to a short column packed with Celiteand silica gel and was eluted with a 1:1:1 mixture of EtOAc-hexane-MeOH(50 mL). The eluate was concentrated and subjected to silica gel columnchromatography (EtOAc-hexane-MeOH, 1:1:1) to provided a gummy solidwhich was dried azeotropically with toluene to give 50 mg (82%) of awhite solid as the product: [α]_(D) +125° (c, 1.01, MeOH); m.p.130°-132° C.; ¹ H NMR (CD₃ OD) δ3.05 (dd, 1H, J=4.3, 11.9 Hz), 3.42 (dd,1H, J=5.3, 11.9 Hz), 3.76-3.89 (m, 2H), 5.19-5.21 (m, 1H), 5.81 (d, 1H,J=7.6 Hz), 6.20-6.23 (m, 1H), 7.01-7.16 (brm, 2H, exchangeable), 7.98(d, 1H, J=7.5 Hz); ¹³ C (CD₃ OD) δ38.5, 64.1, 88.0, 88.9, 95.7, 142.8,157.9, 167.7.

EXAMPLE 18

(1'R,2'S,5'R)-MENTHYL-5R-(5'-FLUOROCYTOSIN-1"-YL)-1,3-OXATHIOLANE-2S-CARBOXYLATE##STR34##

To a suspension of 5-fluorocytosine (155 mg, 1.2 mmol) in CH₂ Cl₂ (1 mL)at room temperature under an argon atmosphere was added, successively,2,4,6-collidine (0.317 mL, 2.4 mmol) and t-butyldimethylsilyltrifluoromethane-sulfonate (0.551 mL, 2.4 mmol). The resultant mixturewas stirred for 15 minutes and a clear solution was obtained. A solutionof (1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2S-carboxylate (330mg, 1 mmol) in CH₂ Cl₂ (0.5 mL) was introduced, followed byiodotrimethylsilane (0.156 mL, 1.1 mmol). Stirring was continued for 3hours. The mixture was diluted with CH₂ Cl₂ (20 mL) and washedsuccessively with saturated aqueous NaHSO₃, water, brine and then wasconcentrated. The residue was taken up in ether-hexanes (1:1, 10mL) andsaturated aqueous NaHCO₃ (2 mL) and stirred at room temperature for 15minutes. The aqueous layer was removed and the organic phase wascentrifuged to afford a white solid which was washed with hexanes (3×5mL) and then dried under vacuum. The product(1'R,2'S,5'R)-menthyl-5R-(5"-fluorocytosin-1"-yl)-1,3-oxathiolane-2S-carboxylate(350 mg, 88%) thus obtained contained about 6% of(1'R,2'S,5'R)-menthyl-5S-(5"-fluorocytosin-1"-yl)-1,3-oxathiolane-2S-carboxylate(NMR). This material was recrystallized from MeOH/CH₂ Cl₂ /benzene togive a crystalline product: [α]_(D) ²⁶ +22° (C, 0.19, MeOH); m.p.216°-218° C., ¹ H NMR (CDCl₃) δ0.78 (d, 3H, J=7Hz), 0.91 (t, 6H, J=7.3Hz), 1.00 (m, 2H), 1.39-2.04 (m, 7H), 3.12 (dd, 1H, J=6.6 Hz, 6.1 Hz),3.52 (dd, 1H, J=4.7 Hz, 6.1 Hz), 4.79 (dt, 1H, J=4.4 Hz, 4.3 Hz), 5.46(S, 1H), 5.75 (bs, 1H, exchangeable), 6.42 (5t, 1H, J=5.0 Hz), 8.10 (bs,1H, exchangeable), 8.48 (d: 1H, J=6.6 Hz); ¹³ C NMR (CDCl₃ -DMSO-d₆):δ16.7, 21.2, 22.4, 23.7, 26.6, 31.8, 34.4, 36.6, 40.5, 47.2, 77.1, 79.1,90.8, 126.3 (d, J=33 Hz), 137.1 (d, J=244 Hz), 154.2, 158.3 (d, J=15Hz), 170.1.

EXAMPLE 19

(1'S,2'R,5'S)-MENTHYL-5S-(5"-FLUOROCYTOSIN-1"-YL)-1,3-OXATHIOLANE-2R-CARBOXYLATE##STR35##

To a suspension of 5-fluorocytosine (180.0 mg, 1.4 mmol) in CH₂ Cl₂ (1mL) at room temperature under an argon atmosphere was added,successively, 2,4,6-collidine (0.46 mL, 3.5 mmol) andt-butyldimethylsilyl trifluoromethane-sulfonate (0.67 mL, 2.9 mmol). Theresultant mixture was stirred for 15 minutes and a clear solution wasobtained. A solution of(1,S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate (414 mg,1.25 mmol) in CH₂ Cl₂ (0.6 mL) was introduced, followed byiodotrimethylsilane (0.18 mL, 1.27 mmol). The resultant mixture wasstirred for 1 hour. The mixture was diluted with CH₂ Cl₂ (20 mL) andwashed successively with saturated aqueous NaHSO₃, water, and brine. Thesolvent was evaporated and the residue was taken up in ether-hexanes(1:1, 10 mL) and saturated aqueous NaHCO₃ (2 mL). Stirring was continuedfor 15 minutes. The aqueous layer was removed and the organic phase wascentrifuged to give a white solid which was washed with hexanes (3×5 mL)and dried under vacuum. This substance, namely(1,S,2,R,5,S)-menthyl-5S-(5"-fluorocytosin-1"-yl)-1,3-oxathiolane-2R-carboxylate(454 mg, 91%) contained about 7% of(1,S,2,R,5'S)-menthyl-5R-(5"-fluorocytosin-1"-yl)-1,3-oxathiolane-2R-carboxylate(as indicated by its ¹ H NMR sepctrum), was recrystallized from benzeneCH₂ Cl₂ --MeOH to give the title compound: [α]_(D) ²⁶ -20° (c,0.072,MeOH); m.p. 220°-222° C. (decomposed), ¹ H NMR (CDCl₃) δ0.80 (d,3H, J=7 Hz), 0.90 (t, 6H, J=7 Hz), 1.0 (m, 2H), 1.39-2.04 (m, 7H), 3.12(dd, 1H, J=6.6 and 6 Hz), 3.52 (dd, 1H, J=5 and 6 Hz), 4.8 (dt, 1H,J=4.4 and 4.3 Hz), 5.46 (s, 1H), 5.78 (bs, 1H, exchangeable), 6.42 (t,1H, J=5 Hz), 8.1 (bs, 1H exchangeable), 8.5 d, 1H, J=6.6 Hz); ¹³ C(CDCl₃) δ16.2, 20.7, 21.9, 23.3, 26.2, 31.4, 34.0, 36.3, 40.1, 46.8,76.7, 78.7, 90.5, 125.9 (d. J=33 Hz), 136.5 (d, J=242 Hz), 153.7, 158.2(d, J=14 Hz), 169.6.

EXAMPLE 20

2S-HYDROXYMETHYL-5R-(5'-FLUOROCYTOSIN-1'-YL)-1,3-OXATHIOLANE ##STR36##

To a suspension of lithium aluminum hydride (10 mg, 0.54 mmol) in THF (1mL) at ambient temperature under an argon atmosphere was slowly added asolution of(1'R,2'S,5'R)-menthyl-5R-(5"-fluorocytosin-1"-yl)-1,3-oxathiolane-2S-carboxylate(54 mg, 0.135 mmol) in THF (2 mL). The reaction mixture was allowed tostir for 30 minutes, then quenched with excess methanol (2 mL), followedby the addition of silica gel (3 g). The resultant slurry was subjectedto silica gel column chromatography (EtOAc-Hexane-MeOH, 1:1:1) toprovide a gummy solid which was dried azeotropically with toluene togive 20.7 mg (63%) of a white solid as the product: [α]_(D) ²⁶ +114° (C,0.12, MeOH); ¹ H NMR (DMSO-d6) δ3.14 (dd, 1H, J=4.3, 11.9 Hz), 3.42 (dd,1H J=5.3, 11.9 Hz), 3.76 (m,2H), 5.18 (m, 1H), 5.42 (t, 1H, J=4.8 Hz),6.14 (m, 1H), 7.59 (br m, 1H, exchangeable), 7.83 (br m, 1Hexchangeable), 8.20 (d, 1H, J=7.66 Hz).

EXAMPLE 21

2R-HYDROXYMETHYL-5S-(5'-FLUOROCYTOSIN-1'-YL)-1,3-OXATHIOLANE ##STR37##

To a stirred THF (2 mL) suspension of lithium aluminum hydride (22 mg,1.13 mmol) at ambient temperature under an argon atmosphere was slowlyadded a solution of (1'R, 2'S,5'R)-menthyl-5S-(5"-fluorocytosin-1"-yl)-1,3-oxathiolane-2R-carboxylate(91 mg, 0.23 mmol) in THF (8 mL). The reaction mixture was allowed tostir for 2 hours, and was quenched by addition of methanol (3 mL),followed by silica gel (5 g). The resultant slurry was stirred for 30minutes. The mixture was then passed through a short pad of Celite andsilica gel eluted with a 1:1:1 mixture of EtOAc-hexane-Methanol (10×5mL). The eluate was concentrated and subjected to silica gel columnchromatography (EtOAc-hexane-methanol, 1:1:1) to give a gummy solid.This solid was dried azeotropically with toluene to give 45 mg (80%) ofthe desired product: [α]_(D) ²⁶ -119° (C, 1.01, MeOH), ¹ H NMR (DMSO-d₆)δ3.14 (dd, 1H, J=4.3, 11.9 Hz), 3.42 (dd, 1H, J=5.3, 11.9 Hz), 3.76 (m,2H), 5.18 (m, 1H), 5.42 (t, 1H, J=4.8 Hz), 6.14 (m, 1H), 7.59 (br m, 1H,exchangeable), 7.83 (br m, 1H exchangeable), 8.20 (d, 1H J=7.66 Hz).

EXAMPLE 22

CIS-2(N-METHYL-N-METHOXYAMINOCARBONYL)-5-(URACIL-1'-YL)-1,3-OXATHIOLANE##STR38##

Trimethylsilyl trifluoromethanesulphonate (TMSOTf) (107 μL, 0.552 mmol)was introduced to a stirred suspension of uracil (31 mg, 0.276 mmol) indichloromethane (1.5 mL) containing collidine (73 μL, 0.552 mmol) underargon atmosphere. The resultant mixture was stirred for 15 minutes toprovide a homogeneous solution. A solution oftrans-2-(N-methyl-N-methoxyaminocarbonyl)-5-acetoxy-1,3-oxathiolane (50mg, 0.23 mmol) in dichloromethane (1 mL) was introduced, followed byiodotrimethylsilane (TMSI) (33 μL, 0.23 mmol). The reaction was allowedto proceed for 2.5 hours and then was quenched with a solution ofsaturated NaHCO₃ and Na₂ S₂ O₃ (1:1). The resulting mixture was stirredfor 5 minutes and then was transferred to a separatory funnel with theaid of more dichloromethane. The aqueous phase was removed and theorganic layer was washed with saturated Na₂ S₂ O₃, water, brine and thenwas dried (Na₂ SO₄). Evaporation of the solvent under reduced pressureafforded the crude product which was triturated with EtOAc-Hexane (1:1)to give 54 mg (87%) of the title compound as a white solid; ¹ H NMR(CDCl₃): δ3.14 (d of d, 1H, J=8.0, 11.8 Hz), 3.23 (s, 3H), 3.38 (d of d,1H, J=4.7, 11.8 Hz), 3.74 (s, 3H), 5.80 (d, 1H, J=8.2 Hz), 5.82 (s, 1H),6.44 (d of d, 1H, J=4.7, 8.0 Hz), 8.64 (d, 1H, J=8.2 Hz), 9.64 (br s,1H).

EXAMPLE 23

CIS- AND TRANS-2-BENZOYL-5-ACETOXY-1,3-OXATHIOLANE ##STR39##

Phenyl glyoxal monohydrate (608 mg, 4.0 mmol) and2,5-dihydroxy-1,4-dithiane (304 mg, 2.0 mmol) were heated for ca. 5minutes at 65° C. until the reagents melted. The reaction mixture wasdiluted with dichloromethane (40 mL). Pyridine (1.32 μL, 16.0 mmol),4-dimethylamino-pyridine (DMAP) (48 mg), and acetyl chloride (0.85 mL,12.0 mmol) were added to the stirred solution at 0° C. The reactionmixture was stirred at room temperature for 4.5 hours and diluted withbrine solution (15 mL). The organic layer was separated, washed withsodium bicarbonate and brine solutions, dried (sodium sulfate), andevaporated to a brown liquid (1.80 g). The residue was purified bysilica gel chromatography eluting with hexanes:EtOAc (3:1) to yield thetrans and cis isomers (2.4:1 ratio) (714 mg, 71%); ¹ H NMR (CDCl₃) δ2.0(s, 3H), 2.14 (s, 3H), 3.15-3.25 (m, 1H), 3.35-3.45 (m, 1H), 6.42 (s,1H), 6.51 (s, 1H), 6.7 (m, 1H), 6.9 (m, 1H), 7.4-7.5 (m, 2H), 7.55-7.65(m, 1H), 7.9-8.0 (m, 2H).

EXAMPLE 24

CIS-2-(1'-PYRROLIDINOCARBONYL)-5-ACETOXY-1,3-OXATHIOLANE ##STR40##

To a solution of 5-acetoxy-oxathiolane-2-carboxylic acid (576 mg, 3.0mmol), pyridine (0.533 mL, 6.60 mmol), and dichloromethane (20 mL) at 0°C., was added oxalyl chloride (0.314 mL, 3.6 mmol). The reaction wasstirred at 0° C. for 30 minutes and then cooled to -70° C. at which timepyrrolidine (0.5 mL, 6.0 mmol) was added in one portion. The reactionwas stirred at room temperature for 2 hours followed by addition of 1NHCl (5 mL). The organic layer was separated, washed with sodiumbicarbonate and brine solutions, dried (sodium sulfate), andconcentrated to yield 0.851 g of crude product. This residue waspurified by silica gel chromatography eluting with EtOAc:hexanes (9:1)to give 616 mg (84%) of the desired product; ¹ NMR (CDCl₃) δ1.80-2.00(m, 4H), 2.11 (s, 3H), 3.20-3.35 (m, 2H), 3.40-3.55 (m, 4H), 5.76 (s,1H), 6.60 (m, 1H).

EXAMPLE 25

CIS-2-CARBOMETHOXY-5-(5'-BROMOURACIL-1'-YL)-1,3-OXATHIOLANE ##STR41##

Bis-trimethylsilyl-acetamide (4 mL, 16.2 mmol) was added to a suspensionof 5-bromouracil (1.5 g, 7.9 mmol) in dichloromethane (10 mL). Thereaction was stirred for 30 minutes, yielding a clear solution. Then adichloromethane solution (5 mL) of2-carbomethoxy-5-acetoxy-1,3-oxathiolane (1.6 g, 7.8 mmol cis:trans 1:2)was added, followed by TMSI (1.1 mL, 7.7 mmol).

The reaction was stirred at ambient temperature for 18 hours and thensequentially treated with saturated aqueous solutions of Na₂ S₂ O₃ andNaHCO₃ to give a white suspension. The suspension was filtered to removethe solid (unreacted base). The filtrate was concentrated and trituratedwith EtOAc-Hex (1:1) to give white solid which was filtered, washed anddried to give 0.98 g (38%) of the product. ¹ H NMR (CDCl₃) δ3.2 (dd, 1H,J=7 and 12 Hz), 3.47 (dd, 1H, J=5 and 12 Hz), 3.87 (s, 1H), 5.50 (s,1H), 6.42 (dd, 1H, J=5 and 7 Hz), 8.72 (s, 1H), 9.19 (br s, 1H).

EXAMPLE 26

CIS-2-HYDROXYMETHYL-5-(6'-CHLOROURACIL-1'-YL)-1,3-OXATHIOLANE ##STR42##

TMSOTf (4.5 mL, 27.3 mmol) was added to a suspension ofbis-O-silyl-6-chlorouracil (9.5 g, 32.6 mmol) and2-carbethoxy-5-acetoxyoxathiolane (6.3 g, 27.4 mmol) in1,2-dichloroethane (40 mL). The resulting clear solution was heatedslowly up to 60° C. and kept at this temperature for 1 hour, duringwhich time a thick precipitate appeared. The reaction was cooled down toambient temperature and the white precipitate was collected afterfiltration, washed and dried to give 3.5 g (42%) of the only cisnucleoside ester product (¹ HNMR). To a tetrahydrofuran (THF) (50 mL)suspension of nucleoside ester product (2.6 g, 8.5 mmol), under argonatmosphere, was slowly added LiBH₄ (0.4 g, 18.6 mmol). The reaction wasstirred for 5 hours, then quenched with methanol. The solvent wasremoved, followed by subjecting the resulting gummy material to columnchromatography (2:2:1, EtOAc-Hex-MeOH, v/v) to yield 1.9 g (85%) of thetitle nucleoside. The overall yield of these two transformations was64%; HPLC purity (96%); mp 202°-204° C.; ¹ H NMR (DMSO-d₆) δ3.09-3.30(1H), 3.38-3.47 (1H), 3.60-3.72 (2H), 4.45 (1H), 5.05-5.09 (1H), 5.27(1H), 5.59-5.62 (1H), 6.71-6.76 (1H); ¹³ C NMR (DMSO-d₆) δ32.6, 63.2,64.2, 84.7, 87.9, 94.4, 106.6, 128.6, 164.4.

EXAMPLE 27

(1'S,2'R,5'S)-MENTHYL-5S-(N-4"-ACETYLCYTOSIN-1"-YL)-1,3-OXATHIOLANE-2R-CARBOXYLATE##STR43##

To a stirred suspension of N-4-acetylcytosine (68 mg, 0.4 mmol) indichloromethane (0.5 mL) containing 2,4,6-collidine (105 μL, 0.8 mmol)under an argon atmosphere was added trimethylsilyltrifluoromethane-sulphonate (155 μL, 0.8 mmol). The resulting mixturewas stirred for 15 minutes to give a homogeneous solution. Thesubstrate,(1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate (110 mg,0.333 mmol) was introduced into the above solution in one batch. In aseparate flask equiped with a condensor, a solution ofhexamethyldisilazane (34 μL, 0.167 mmol) and iodine (42 mg, 0.167 mmol)in dichloromethane (0.5 mL) was refluxed under argon atmosphere for 30minutes. After it had cooled to room temperature, the purple solutionformed was transferred, via a syringe, into the mixture containing thesubstrate and silylated base.

The reaction mixture was kept at room temperature for 7 hours and thenwas quenched with a solution of a 1:1 mixture of saturated NaHCO₃ andNa₂ S₂ O₃. The resulting mixture was stirred for 5 minutes and then wastransferred to a separatory funnel with the aid of more dichloromethane.The aqueous phase was removed and the organic layer was washed withsaturated. Na₂ S₂ O₃, water, brine and then was dried (Na₂ SO₄). Thesolvent was removed under reduced pressure to provide 153 mg of crudeproduct. To determine the ratio of thecis-[(1'S,2'R,5'S)-menthyl-5S-(N-4"-acetylcytosin-1"-yl)-1,3-oxathiolane-2R-carboxylate]andtrans-[(1'S,2'R,5'S)-menthyl-5R-(N-4"-acetylcytosin-1"-yl)-1,3-oxathiolane-2R-carboxylate]product isomers, the crude product was subjected to ¹ H NMR analysis inCDCl₃. Judging from the signals of the C6 protons of the cytosinemoiety, the ratio of cis [δ8.70 (d, J=7.6 Hz)] to trans [δ7.79 (d, J=7.6Hz)] was determined to be 7:1.

EXAMPLE 28

CIS-2-CARBOXYL-5-(URACIL-1'-YL)-1,3-OXATHIOLANE ##STR44##

Iodotrimethylsilane (118 μL, 0.832 mmol) was added to a stirredsuspension of bis-trimethylsilyluracil (122 mg, 0.475 mmol) andtrans-2-carboxyl-5-acetoxy-1,3-oxathiolane (76 mg, 0.396 mmol) indichloromethane (2.5 mL) containing collidine (53 μL, 0.396 mmol). Theresultant mixture was stirred for 18 hours at room temperature underargon atmosphere and then was quenched by the addition of 5 mL of a 0.5Msolution of sodium carbonate. The aqueous phase was acidified with 1MHCl solution to pH 4, followed by extraction with tetrahydrofuran (3×6mL). The combined extract was dried over MgSO₄ and the solvent wasremoved under reduced pressure. The crude product obtained wastriturated with dichloromethane to provide a white suspension. The whitesolid was isolated by centrifugation and was dried under vacuum toafford 27 mg of the desired product whose ¹ H NMR spectrum indicated thepresence of a small amount of uracil (ca. 10%) and an isomeric purity of≧95%. The title compound displayed the following spectralcharacteristics: ¹ H NMR (DMSO d₆) δ: 2.26 (d of d, 1H, J=4.9, 12.3 Hz),3.49 (d of d, 1H, J=5.2, 12.4 Hz), 5.57 (s, 1H), 5.71 (d of d, 1H,J=2.2, 8.0 Hz; this signal collapsed to a doublet on treatment with D₂ O(J=8.2 Hz)), 6.29 (t, 1H, J=5.2 Hz), 8.07 (d, 1H, J=8.2 Hz), 11.41 (brs, 1H, exchanged with D₂ O).

EXAMPLE 29

CIS 2-(1'-PYRROLIDINOCARBONYL)-5-(URACIL-1'-YL)-1,3-OXATHIOLANE##STR45##

Iodotrimethylsilane (37 μL, 1 equivalent) was added to a stirredsolution of cis 2-(1'-pyrrolidinocarbonyl)-5-acetoxy-1,3-oxathiolane (64mg, 0.26 mmol) and bis-trimethylsilyluracil (80 mg, 1.2 equivalents) indichloromethane (1.5 mL) under argon atmosphere. The reaction mixturewas kept for 1 hour and 20 minutes at room temperature. The reaction wasquenched with a solution of a 1:1 mixture of saturated Na₂ S₂ O₃ andNaHCO₃ (2 mL), followed by dilution with dichloromethane (4 mL). Theresultant mixture was stirred for 5 minutes and then was transferred toa separatory funnel with the aid of more dichloromethane. The aqueousphase was removed and the organic phase was washed with water, brine,and dried over anhydrous Na₂ SO₄. Removal of the solvent under reducedpressure and subjection of the crude product thus obtained to columnchromatography (7% MeOH-EtOAc) afforded the 74 mg (95%) of the titlecompound; ¹ HNMR (CDCl₃): δ1.85-2.00 (m, 2H), 2.00-2.15 (m,2H),3.25-3.70 (m, 6H), 5.61 (s, 1H), 5.80 (d of d, 1H, J=2.3, 8.2 Hz), 6.44(d of d, 1H, J=4.8, 7.0 Hz), 8.29 (br s, 1H), 8.88 (d, 1H, J=8.1 Hz).

EXAMPLE 30 CIS 2-BENZOYL-5-(URACIL-1'-YL)-1,3-OXATHIOLANE ##STR46##

Trimethylsilyl trifluoromethanesulphonate (92 μL, 0.475 mmol) wasintroduced to a stirred suspension of uracil (50 mg, 0.238 mmol) indichloromethane (1.5 mL) containing collidine (63 μL, 0.475 mmol) underargon atmosphere. The resultant mixture was stirred for 15 minutes toprovide a homogeneous solution. A mixture (2.4:1, trans:cis) of2-benzoyl-5-acetoxy-1,3-oxathiolane (50 mg, 0.198 mmol) was added as asolution in dichloromethane (1.5 mL), followed by iodotrimethylsilane(28 μL, 0.198 mmol). The reaction was allowed to proceed for 22 hoursand then was quenched with a solution of a 1:1 mixture of saturatedNaHCO₃ and Na₂ S₂ O₃. The resulting mixture was stirred for 5 minutesand then was transferred to a separatory funnel with the aid of moredichloromethane. The aqueous phase was removed and the organic layer waswashed with saturated Na₂ S₂ O₃, water, brine and then was dried (Na₂SO₄). Thin layer chromatography analysis of the crude product indicatedthat small amount of the starting material remain unreacted. The crudeproduct was triturated with EtOAc to provide 26 mg (43%) of the titlecompound as a white solid; ¹ H NMR (DMSO): δ3.19 (d of d, 1H, d of d,J=6.8, 12.1 Hz), 3.60 (d of d, 1H, J=5.1, 12.2 Hz), 5.77 (d, 1H, J=8.2Hz), 6.38 (d of d, 1H, J=5.2, 6.9 Hz), 6.81 (s, 1H), 7.52-7.64 (m, 2H),7.66-7.76 (m, 1H), 7.94-8.04 (m, 2H), 8.22 (d, 1H, J=8.1 Hz), 11.44 (brs, 1H).

EXAMPLE 31

(1'R,2'S,5'R)-MENTHYL-5S-(CYTOSIN-1"-YL)-1,3-OXATHIOLANE-2R-CARBOXYLATE##STR47##

A 12:1 mixture of (1'R,2'S,5'R)-menthyl5S-(N-4"-acetylcytosin-1"-yl)-oxathiolane-2R-oxathiolane carboxylate(cis isomer) and (1'R,2'S,5'R)-menthyl5R-(N-4"-acetylcytosin-1"-yl)-oxathiolane-2R-oxathiolane carboxylate(trans isomer) (47 mg,0.11 mmol) was dissolved in dichloromethane (0.5mL) and 2-propanol (1 mL). Trifluoroacetic acid (0.2 mL) was added tothis solution and the resultant mixture was heated at 60° C. for 2 hoursand then was kept at room temperature for 14.5 hours. The reactionmixture was diluted with dichloromethane and washed with saturatedNaHCO₃ solution, water, brine, and then was dried (anhydrous Na₂ SO₄).The solvent was removed under reduced pressure and the product obtainedwas dried under vacuum to afford 40 mg (95%) of the title compounds. The¹ H NMR spectrum of the above material suggested a purity of ≧97%. Basedon the signals derived from the C₆ hydrogen of the cytosine moietypresent in both of the isomers, the 12:1 ratio of the cis [(δ8.38 (d,J=7.3 Hz)] and trans [(δ7.48 (d, J=7.3 Hz)] nucleosides was maintained.The major compound was obtained by fractional crystallization withmethanol and displayed physical properties identical to those reportedin this example.

EXAMPLE 32

(1'S,2'R,5'S)-MENTHYL-5S-(N-4"-ACETYLCYTOSIN-1"-YL)-1,3-OXATHIOLANE-2R-CARBOXYLATE##STR48##

(1'S,2'R,5'S)-menthyl 5R-acetoxy-1,3-oxathiolane-2R-carboxylate (55 mg,0.166 mmol) in dichloromethane (0.5 mL) and iodotrimethylsilane (0.026mL, 0.166 mmol) were added to monosilylated N-4-acetylcytosine (59 mg,0.198 mmol), generated by refluxing N-4-acetylcytosine in1,1,1,3,3,3-hexamethyldisilazane (HMDS) overnight in the presence ofcatalytic amount of ammonium sulfate and subsequently removing HMDS, indichloromethane (0.5 mL) under argon atmosphere at room temperature. Thestirring was continued for 19 hours and thin layer chromatography showedalmost complete consumption of the starting oxathiolane. The reactionmixture was diluted with dichloromethane, washed with saturated aqueoussodium bicarbonate, aqueous sodium thiosulfate and brine, dried oversodium sulfate, concentrated and dried to afford 70 mg (100%) of crudeproducts. ¹ H NMR suggested cis:trans ratio at 15:1 and the presence ofca. 4.6% of urnreacted oxathiolane. ¹ H NMR (CDCl₃): 0.78 (d,3H),0.80-2.10 (m, 15H), 2.27 (s, 3H), 3.12-3.30 (m, 1H) 3.52-3.78 (m, 1H),4.78 (m, 1H), 5.51 (s, 0896H), 5.60 (s, 0.046H), 5.82 (s, 0.058H), δ6.42(t, 0.896H), 6.63 (dd, 0.046 H), 6.68 (d, 0.058H), 7.47 (d, 0.954H),7.77 (d, 0.058H), 8.70 (d, 0.896H). The major compound was isolated bycrystallization from methanol or trituration with ethylacetate-ethermixtures.

EXAMPLE 33

(1'S,2'R,5'S)-MENTHYL-5S-(N-4"-ACETYLCYTOSIN-1"-YL)-1,3-OXATHIOLANE-2R-CARBOXYLATE##STR49##

2,6-lutidine (0.023 mL, 0.199 mmol) and trimethylsilyltrifluoromethanesulfonate (0.038 mmol, 0.199 mmol) were added toN-4-acetylcytosine (30.5 mg, 0.199 mmol) in dichloromethane (0.2 mL) atroom temperature under argon atmosphere. The mixture was stirred for 20minutes and a solution of(1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate (55 mg,0.166 mmol) in dichloromethane (0.3 mL) and iodotrimethyl-silane (0.026mL, 0.166 mmol) were introduced successively. The stirring was continuedfor 2.5 hour and thin layer chromatography showed complete consumptionof the starting oxathiolane. The reaction mixture was diluted withdichloromethane, washed with saturated aqueous sodium bicarbonate,aqueous sodium thiosulfate and brine, dried over sodium sulfate,concentrate and dried to afford 70 mg (100%) of crude products. ¹ H NMRsuggested cis:trans ratio at 10:1 and no other impurity detectable bythe spectrum. ¹ HNMR (CDCl₃): 0.78 (d, 3H), 0.80-2.10 (m, 15H), 2.27 (s,3H), 3.16 (dd, 0.91H), 3.25 (d, 0.09H), 3.63 (dd, 0.91H), 3.74 (dd,0.09H), 4.78 (m, 1H), 5.51 (s, 0.91H), 5.82 (s, 0.09H); 8 6.42 (t,0.91H), 6.68 (d, 0.09H), 7.47 (d, 1H), 7.77 (d, 0.09H), 8.70 (d, 0.91H).

EXAMPLE 34

CIS- AND TRANS-ISOPROPYL 5-ACETOXY-1,3-OXATHIOLANE-2-CARBOXYLATE##STR50##

A solution of cis- and trans 5-acetoxy-1,3-oxathiolane-2-carboxylic acid(260 mg, 1.3528 mmol) and isopropanol (0.11 mL, 1.3528 mmol) indichloromethane (4 mL) at 0° C. was treated with dicyclohexylcarboiimide(DCC) (279 mg, 1.3528 mmol) in dichloromethane (1 mL) and 4dimethylaminopyridine (DMAP) (14 mg, 0.135 mmol). The mixture wasstirred at room temperature overnight, then diluted with ether andfiltered through a Celite® pad. The filtrate was concentrated and theresidue was chromatographed on silica gel with ethyl acetate-hexane togive the products as a colorless oil (263 mg, 83%). ¹ H NMR (CDCl₃):δ1.26 (6H, d) ; 2.10, 2.11 (3H, s) ; 3.13-3.46 (2H, m); 5.05 (1H, m);5.60, 5.61 (1H, s); 6.63 (0.54H, m); 6.78 (0.46H, d).

EXAMPLE 35

CIS-ISOPROPYL-5-(CYTOSIN-1'-YL)-1,3-OXATHIOLANE-2-CARBOXYLATE ##STR51##

2,4,6-collidine (0.23 mL, 1.74 mmol) and t-butyl-dimethylsilyltrifluoromethanesulfonate (0.4 mL, 1.74 mmol) were added to a suspensionof cytosine (96.7 mg, 0.87 mmol) in dichloromethane (0.8 mL) at roomtemperature under argon atmosphere. The mixture was stirred for 25minutes and a solution of cis:trans (1.2:1) isopropyl5-acetoxy-1,3-oxathiolane-2-carboxylate (168 mg, 0.717 mmol) indichloromethane (0.8 mL) and a solution of iodotrimethylsilane (0.114mL, 0.788 mmol) were introduced successively. Stirring was continued forone hour and the reaction mixture was diluted with dichloromethane,washed with saturated aqueous sodium thiosulfate, water and brine, driedover sodium sulfate and concentrated. The residue was triturated withether-hexane (1:1, 7 mL) and saturated aqueous sodium bicarbonate (1.5mL). The aqueous layer was removed and the remaining mixture wascentrifuged.

The solid was washed twice with hexanes and the washings were combinedwith centrifugate, washed with 1N HCl, water and brine, dried andconcentrated to give the unreacted starting material in virtually pureform (64 mg, 38%, cis:trans=:1:9). The white solid was dried and gavethe products as a cis:trans mixture in 12:1 ratio (122.6 mg, 60%). ¹ HNMR (CDCl₃): δ1.30 (t, 6H), 3.11 (dd, 1H), 3.52 (dd, 1H), 5.11 (m, 1H),5.45 (s, 1H), 5.82 (d, 1H), 6.47 (dd, 0.92H), 6.72 (m, 0.08H), 7.49 (d,0.08H), 8.32 (d, 0.92H).

EXAMPLE 36

CIS- AND TRANS-T-BUTYL 5-ACETOXY-1,3-OXATHIOLANE-2-CARBOXYLATE ##STR52##

A solution of cis- and trans-5-acetoxy-1,3-oxathiolane-2-carboxylic acid(176 mg, 0.915 mmol) and t-butanol (0.095 mL, 0.915 mmol) indichloromethane (4 mL) at 0° C. was treated with DCC (207 mg, 1 mmol) indichloromethane (1 mL) and DMAP (11 mg, 0.09 mmol). The mixture wasstirred at room temperature overnight, then diluted with ether andfiltered through a Celite® pad. The filtrate was concentrated and theresidue was chromatographed on silica gel with ethyl acetate-hexane togive the products as a colorless oil (175 mg, 77%). ¹ H NMR (CDCl₃):δ1.46 (9H, d); 2.07, 2.09 (3H, s); 3.10-3.44 (2H, m); 5.50, 5.52 (1H,s); 6.60 (0.42H, m); 6.74 (0.58H, d).

EXAMPLE 37

CIS-T-BUTYL-5-(CYTOSIN-1'-YL)-1,3-OXATHIOLANE-2-CARBOXYLATE ##STR53##

2,4,6-collidine (0.187 mL, 1.4 mmol) and t-butyl-dimethylsilyltrifluoromethanesulfonate (0.325 mL, 1.4 mmol) were added to asuspension of cytosine (78.6 mg, 0.7 mmol) in dichloro-methane (0.6 mL)at room temperature under argon atmosphere. The mixture was stirred for25 minutes and a mixture of cis and trans (1:1.4) t-butyl5-acetoxy-1,3-oxathiolane-2-carboxylate (146.5 mg, 0.59 mmol) indichloromethane (0.6 mL) and iodotrimethylsilane (0.092 mL, 0.65 mmol)were introduced successively. Stirring was continued for one hour andthe reaction mixture was diluted with dichloromethane, washed withsaturated aqueous sodium thiosulfate, water and brine, dried over sodiumsulfate and concentrated. The residue was triturated with ether-hexanes(1:1, 7 mL) and saturated aqueous sodium bicarbonate (1.5 mL). Theaqueous layer was removed and the remaining mixture was centrifuged. Thesolid was washed twice with hexanes and the washings were combined withthe centrifugate, washed with 1N HCl, water and brine, dried andconcentrated to give the unreacted starting material in virtually pureform (77 mg, 52.6%, cis:trans=1:11). The white solid was dried and gavethe products as a cis:trans mixture in 16:1 ratio (82.6 mg, 46.4%). ¹ HNMR (CDCl₃): δ1.50, 1.52 (s, 9H), 3.12 (dd, 0.94H), 3.20 (dd, 0.06H),3.52 (dd, 0.94H), 3.72 (dd, 0.06H), 5.37 (s, 0.94H), 5.75 (s, 0.06H),5.83 (d, 1H), 6.44 (dd, 0.94H), 6.71 (d, 0.06H), 7.49 (d, 0.06H), 8.38(d, 0.98H).

EXAMPLE 38

CIS- AND TRANS-2-N,N-DIETHYLAMINOCARBONYL-5-ACETOXY-1,3-OXATHIOLANE##STR54##

A solution of cis- and trans-5-acetoxy-1,3-oxathiolane-2-carboxylic acid(119 mg, 0.62 mmol) and diethylamine (0.07 mL, 0.68 mmol) indichloromethane (2 mL) at 0° C. was treated with DCC (140 mg, 0.68 mmol)in dichloromethane (1 mL) and DMAP (7.6 mg, 0.06 mmol). The mixture wasstirred at room temperature overnight, then diluted with ether andfiltered through a Celite® pad. The filtrate was concentrated and theresidue was chromatographed on silica gel with ethyl acetate-hexane togive the products as a colorless oil (84.5 mg, 55%). ¹ H NMR (CDCl₃):δ1.10, 1.40 (6H, t); 2.07, 2.10 (3H, s); 3.15-3.56 (6H, m); 5.80, 5.87(1H, s); 6.58 (0.53H, m); 6.83 (0.47H, d).

EXAMPLE 39

CIS-2-N,N-DIETHYLAMINOCARBONYL-5-(CYTOSIN-1'-YL)-1,3-OXATHIOLANE##STR55##

2,4,6-collidine (0.108 mL, 0.82 mmol) and t-butyl-dimethylsilyltrifluoromethanesulfonate (0.188 mL, 0.82 mmol) were added to asuspension of cytosine (45.5 mg, 0.41 mmol) in dichloromethane (0.4 mL)at room temperature under argon atmosphere. The mixture was stirred for25 minutes and a mixture of cis and trans (1.12:1)2-N,N-diethylamindocarbonyl-5-acetoxy-1,3-oxathiolane (84 mg, 0.34 mmol)in dichloromethane (0.4 mL) and a solution of iodotrimethylsilane (0.053mL, 0.375 mmol) were introduced successively. Stirring was continued forone hour and the reaction mixture was diluted with dichloromethane,washed with saturated aqueous sodium thiosulfate, water and brine, driedover sodium sulfate and concentrated. The residue was triturated withether-hexane (1:1, 7 mL) and saturated aqueous sodium bicarbonate (1.5mL). The aqueous layer was removed and the remaining mixture wascentrifuged. The solid was washed twice with hexanes and the washingswere combined with centrifugate, washed with 1N HCl, water and brine,dried and concentrated to give the unreacted starting material invirtually pure form (17 mg, 20%, trans only). The white solid was driedto give the products as a cis:trans mixture in 24:1 ratio (47.5 mg,47.5%). ¹ H NMR (DMSO-d₆): δ1.04 (t, 3H, J=7 Hz), 1.12 (t, 3H, J=7 Hz),3.17 (dd, 1H, J=5 Hz, 9 Hz), 3.30 (m, 4H), 3.53 (dd, 1H, J=5 Hz, 9 Hz),5.74 (d, 1H, J=7 Hz), 5.96 (s, 1H), 6.28 (t, 0.96H, J=5 Hz), 6.62 (m,0.04H), 7.16 (b.s., NH), 7.22 (b.s., NH), 7.60 (d, 0.04H), 8.46 (d,0.96H, J=7 Hz).

EXAMPLE 40

1'S,2'R,5'S)-MENTHYL-1,3-OXATHIOLANE-2R-CARBOXYLATE ##STR56##

To a mixture of(1'S,2'R,5'S)-menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate (2.01 g,6.08 mmol) and triethylsilane (9.67 mL, 60.05 mmol) at room temperatureunder argon atmosphere was added trimethylsilyltrifluoromethanesulfonate (1.17 mL, 6.04 mmol). The reaction mixture wasstirred at room temperature for 12 hours, then diluted withdichloromethane, washed with saturated aqueous solution of sodiumbicarbonate, dried over anhydrous sodium sulfate, and evaporated todryness in vacuo to afford crude product. Subsequent chromatography onsilica gel using hexane-ethyl acetate as eluate gave the product ascolourless oil (1.33 g, 80.5%) ¹ H NMR (CDCl₃): δ0.75-2.10 (m, 15H),2.97-3.20 (m, 2H), 4.2014.40 (m, 2H), 4.72 (dr, 1H), 5.45 (s, 1H)[α]_(D) +104° (c 1.16, CHCl₃).

EXAMPLE 41

(1'S,2'R,5'S)-MENTHYL-4R-HYDROXY-1,3-OXATHIOLANE-2R-CARBOXYLATE AND(1'S,2'R,5'S)-MENTHYL-4S-HYDROXY-1,3-OXATHIOLANE-2R-CARBOXYLATE##STR57##

A mixture of (1'S,2'R,5'S)-menthyl-1,3-oxathiolane-2R-carboxylate (0.500g, 1.84 mmol) and benzoylperoxide (0.489 g, 97%, 1.96 mmol) in 20 mLbenzene was heated to reflux for 6 hours. The organic solvent wasremoved in vacuo and the residue was diluted with dichloromethane,washed with saturated aqueous solution of sodium bicarbonate, dried overanhydrous sodium sulfate, and evaporated to dryness in vacuo to affordcrude benzoate product. Subsequent chromatography by using hexane-ethylacetate as eluate gave the benzoate as a solid (0.21 g, 30.3%). Themixture of the benzoate (0.200 g, 0.531 mmol) and potassium carbonate(0.073 g, 0.532 mmol) in THF--MeOH--H₂ O (4 mL/5 mL/2 mL) was stirred at0° C. for 7 hours and organic solvent was removed in vacuo. The residuewas diluted with H₂ O (7 mL), extracted with ether (10 mL), acidifiedwith aqueous HCl, and extracted with dichloromethane. Thedichloromethane layer was dried over sodium sulfate and evaporated todryness in vacuo to afford crude product. Subsequent chromatographyusing hexane ether as eluent gave the product as a solid (67 mg, 43.7%)¹ H NMR (CDCl₃): δ0.75-2.10 (m, 15H), 4.03-4.83 (m, 2H), 5.52-5.75 (m,2H).

EXAMPLE 42

(1'S,2'R,5'S)-MENTHYL-4R-CHLORO-1,3-OXATHIOLANE-2R-CARBOXYLATE AND(1'S,2'R,5'S)-MENTHYL-4S-CHLORO-1,3-OXATHIOLANE-2R-CARBOXYLATE ##STR58##

To a mixture of(1'S,2'R,5'S)-menthyl-4R-hydroxy-1,3-oxathiolane-2R-carboxylate and(1,S,2'R,5'S)-menthyl-4S-hydroxy-1,3-oxathiolane-2R-carboxylate (40mg,0.138 mmol) and methytrifluoromethansulfonyl chloride (18.24 μL, 0.239mmol) in dichloromethane (5 mL) at room temperature under argonatmosphere was added triethylamine (57.99 mL, 0.416 mmol). The reactionmixture was stirred at room temperature for 2 hours then diluted withdichloromethane, washed with saturated aqueous solution of sodiumbicarbonate, dried over anhydrous sodium sulfate, and evaporated todryness in vacuo to afford crude product. Subsequent chromatography byusing hexane ether as eluent gave the product as two diastereomers (18mg, 42.3%, 14.6 mg, 34.2%) epimeric at C4. ¹ H NMR CDCl₃): δ0.75-2.05(m, 15H), 4.55 (m, 1H), 4.69 (m, 1H), 5.75 (m, 1H), 5.80 (m, 1H);δ0.75-2.10 (m, 15H), 4.33 (m, 1H), 4.78 (m, 1H), 5.56 (s, 1H), 5.68 (m,1H).

EXAMPLE 43

CIS 2-CARBOETHOXY-4-ACETOXY-1,3-DIOXOLANE ##STR59##

A 2.5:1 mixture of cis and trans-2-carboethoxy-4-acetyl-1,3-dioxolane(406 mg, 2.16 mmol), 85% meta-chloroperbenzoic acid (mCPBA) (68 mg, 3.81mmol) and sodium carbonate (389 mg, 3.67 mmol) in dry dichloromethane(10 mL) was stirred under argon for. 16 hours at room temperature. Theresultant suspension was diluted with dichloromethane and water andstirred for 10 minutes. The aqueous phase was removed and the organicphase was washed successively with saturated sodium thiosulfate, water,brine and then was dried over anhydrous magnesium sulfate. The solventwas removed under reduced pressure and the crude product thus obtainedwas subjected to flash column chromatography (30% EtOAc-Hexanes) to givethe title compound (11% yield) which displayed the following spectralcharacteristics; ¹ H NMR (CDCl₃): δ1.31 (t, 3H, J=7.2 Hz), 2.07 (s, 1H),4.15 (d of d, 1H, J=4.5, 9.1 Hz), 4.21-4.29 (m, 3H), 5.42 (s, 1H), 6.39(d of d, 1H, J=2.4, 4.5 Hz); ¹³ C NMR (CDCl₃): δ14.05, 20.97, 29.69,71.34, 94.04, 99.80, 167.19, 170.11.

EXAMPLE 44

TRANS 2-CARBOETHOXY-4-ACETOXY-1,3-DIOXOLANE ##STR60##

A 2.5:1 mixture of cis and trans-2-carboethoxy-4-acetyl-1,3-dioxolane(406 mg, 2.16 mmol), 85% mCPBA (68 mg, 3.81 mmol) and sodium carbonate(389 mg, 3.67 mmol) in dry dichloromethane (10 mL) was stirred underargon for 16 hours at room temperature. The resultant suspension wasdiluted with dichloromethane and water and stirred for 10 minutes. Theaqueous phase was removed and the organic phase was washed successivelywith saturated sodium thiosulfate, water, brine and then was dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure and the crude product thus obtained was subjected to flashcolumn chromatography (30% EtOAc-Hexanes) to give the title compound(49% yield) which displayed the following spectral characteristics; ¹ HNMR (CDCl₃): δ1.29 (t, 3H, J=7.2 Hz), 2.09 (s, 1H), 4.12 (d of d, 1H,J=0.9, 9.1 Hz), 4.19-4.31 (m, 3H), 5.53 (s, 1H), 6.48 (d of d, 1H,J=0.9, 3.9 Hz).

EXAMPLE 45

CIS AND TRANS 2-CARBOETHOXY-4-(THYMIN-1'-YL)-1,3-DIOXOLANE ##STR61##

To a stirred suspension of thymine (44.5 mg, 0.353 mmol) indichloromethane (1 mL) containing 2,6-lutidine (82 μL, 0.706 mmol) underan argon atmosphere was added trimethylsilyl trifluoromethanesulphonate(136 μL, 0.706 mmol). The resulting mixture was stirred for 15 minutesto give a homogeneous solution. A solution of the substrate, ethyl4-acetoxy-1,3-dioxolane-2-carboxylate (60 mg, 0.294 mmol) indichloromethane (1 mL) and iodotrimethylsilane (42 μL, 0.294 mmol) wassequentially introduced into the above solution. The reaction mixturewas stirred at room temperature for 5 hours and then was quenched with ahalf-saturated solution of Na₂ S₂ O₃ (2 mL), followed by dilution withdichloromethane (5 mL). The resulting mixture was stirred for 5 minutesand then was transferred to a separatory funnel with the aid of moredichloromethane. The aqueous phase was removed and the organic layer waswashed with saturated Na₂ S₂ O₃, water, 1M HCl, brine and then was dried(Na₂ SO₄). The solvent was removed under reduced pressure to provide thecrude product. This material was suspended in dichloromethane (˜1.5 mL)and then was triturated with a 1:1 mixture of EtOAc-Hexane (˜6 mL) togive 25 mg of the cis nucleoside as a white solid; ¹ H NMR (DMSO de):δ1.23 (t, 3H, J=7.1 Hz), 1.78 (d, 3H, J=l Hz), 4.15-4.30 (m, 4H), 4.38(d of d, 1H, J=2.3, 9.8 Hz), 5.33 (s, 1H), 6.33 (d of d, 1H, J=2.3, 5.8Hz), 7.52 (d, 1H, J=1.1, Hz), 11.42 (br s, 1H). The triturate wasconcentrated and subjected to column chromatography (70% EtOAc-Hexane)to afford 26 mg of the two nucleoside as a 1:1 mixture; ¹ H NMR (CDCl₃):δ1.33 (t, 1.5H, J=7.2 Hz), 1.35 (t, 1.5H, J=7.2 Hz), 1.91-1.99 (twooverlapping d, 3H), 4.16 (d of d, 0.5H, J=l. 9, 9.7 Hz), 4.20-4.38 (m,3H), 4.53 (d of d, 0.5H, J=5.8, 9.7 Hz), 5.30 (s, 0.5H), 5.72 (s, 0.5H),6.44 (d of d, 0.5H, J=3.3, 5.4 Hz), 6.60 (d of d, 0.5H, J=2.0, 5.8 Hz),7.10 (d, 0.5H, J=1.3 Hz), 7.75 (d, 0.5H, J=1.3 Hz), 9.40 (br s, 0.5H),9.43 (br s, 0.5H).

EXAMPLE 46

CIS AND TRANS 2-CARBOETHOXY-4-(N-4'-ACETYLCYTOSIN-1'-YL)-1,3-DIOXOLANE##STR62##

To a stirred suspension of N-acetylcytosine (66 mg, 0.430 mmol) in dryCH₂ Cl₂ (1.5 mL) under an argon atmosphere was added, successively,2,6-lutidine (100 μL, 0.859 mmol) and trimethylsilyItrifluoromethanesulphonate (166 μL, 0.859 mmol). The resultant mixturewas stirred for 25 minutes to produce a homogeneous solution. A solutionof a 4:1 mixture of cis and trans-2-carboethoxy-4-acetoxy-1,3-dioxolane(73 mg, 0,358 mmol) in CH₂ Cl₂ (1 mL) was then introduced, followed byiodotrimethylsilane (51 μL, 0.358 mmol). The reaction was allowed toproceed for 16 hours and then was quenched with saturated sodiumthiosulfate. The resulting mixture was diluted with CH₂ Cl₂ and waswashed successively with saturated sodium thiosulfate, water, brine, andthen was dried over anhydrous magnesium sulfate. Removal of the solventunder reduced pressure gave the crude product which was purified byflash column chromatography (2% MeOH--EtOAc) to afford 44% of the titlecompounds as a 3:1 mixture of the cis and trans isomers; ¹ H NMR(CDCl₃): δ1.34 (t, 3H, J=7.0 Hz), 2.28 (s, 0.75H), 2.29 (s, 0.25H),4.21-4.35 (m, 3H), 4.36 (d of d, 0.75 H, J=5.2, 9.9 Hz), 4.59 (d of d,0.25H, J=5.2, 9.9 Hz), 5.39 (s, 0.75H), 5.77 (s, 0.25H), 6.24 (d of d,0.75H, J=2.8, 5.1 Hz), 6.39 (d of d, 0.25H, J=1.7, 5.1 Hz), 7.49 (2overlapping doublets, 1H), 7.79 (d, 0.25H, J=7.6 Hz), 8.40 (d, 0.75H,J=7.6 Hz), 9.95 (br s, 1H).

EXAMPLE 47

(±)-CIS AND TRANS-5-ACETOXY-1,3-OXATHIOLANE-2-CARBOXYLIC ACID ##STR63##

Trans-5-hydroxy-1,3-oxathiolane-2-carboxylic acid (250 g, 1.67 mol) wasadded, in portions, to a stirred solution of acetic anhydride (0.625 L,6.62 mol) and methanesulphonic acid (5 mL, 77 mmol) at room temperature.The resultant clear solution was stirred at room temperature for 60minutes, slowly added to stirred aqueous 0.03M sodium bicarbonatesolution (2.5L) and then the mixture was stirred for a further 60minutes. Sodium chloride (750 g, 12.83 mol) was added and the mixturewas stirred for a further 30 minutes, clarified, and then extracted withisopropyl acetate (1×1.25 L, 3×0.625 L). The combined extracts wereconcentrated to 1.25 L under reduced pressure. Xylene (2.5 L) was addedand the mixture reconcentrated to 1.25 L under reduced pressure. Thexylene addition/reconcentration procedure was repeated and the resultantsuspension was cooled to room temperature and stirred for 18 hours. Thesolid was collected by vacuum filtration, washed with xylene (2×0.25 L)and dried, in vacuo, at 40°-45° to give the title compound (265 g, 83%)which was shown, by comparison of ¹ H NMR spectra, to be a 65:35 mixtureof the compounds of Examples 3 and 4.

EXAMPLE 48

5R-ACETOXY-1,3-OXATHIOLANE-2R-CARBOXYLIC ACID, SALT WITH1S,2R-α-(1-AMINOETHYL)BENZENEMETHANOL (1:1) ##STR64##

a) A solution of 1S,2R-α-(1-aminoethyl)benzenemethanol (125.9 g, 0.83mol) in isopropyl acetate (0.5 L) was added to a stirred solution of (±)cis-/trans-5-acetoxy-1,3-oxathiolane-2-carboxylic acid (Example 47; 400g, 2.08 mol), in isopropyl acetate (4.2 L), at room temperature under anitrogen atmosphere. The resultant solution was stirred for 10 minutes,seeded with authentic product (0.4 g) and stirred for a further 4 hoursat room temperature. The suspension was stirred at 15°-18° for 17 hoursand the solid was collected by vacuum filtration, washed with isopropylacetate (1 x. 0.4 L, 1×0.2 L) and dried, in vacuo, at 45° to give thetitle compound (205.9 g, 28%). [α]_(D) +34° (MeOH), mp 151°-2° (decomp),δ(DMSO-D₆) 0.91 (d, 3H, J=6.8 Hz), 2.05 (s, 3H), 3.04 (d, 1H, J=11 Hz),3.32 (dd, 1H, J=4.2 Hz), 3.40 (dg, 1H, J=6.8, 2.4 Hz), 4.97 (d, 1H,J=2.4 Hz), 5.34 (s, 1H), ca. 6.4 (br, 1H), 7.2-7.4 (m, 5H), ca. 8.3 (br,3H).

b) A solution of 1S,2R-α-(1-aminoethyl)benzenemethanol (177 mg, 1.17mmol) in isopropyl acetate (1 mL) was added to a stirred solution of(±)-trans-5-acetoxy-1,3-oxathiolane-2-carboxylic acid (500 mg, 2.60mmol) in isopropyl acetate (6 mL) at 25°-30°, and further isopropylacetate (0.5 mL) was added. Crystallisation commenced after 5 minutes.The suspension was stirred at 25°-30° for 18 hours and then the solidwas collected by vacuum filtration, washed with isopropyl acetate (1 mL)and dried, in vacuo, at 40° to give the title compound (353 mg, 40%), asshown by comparison of its ¹ H NMR spectrum with that of part (a).

EXAMPLE 49

(-)-TRANS-5-ACETOXY-1,3-OXATHIOLANE-2-CARBOXYLIC ACID ##STR65##

5 M-Aqueous hydrochloric acid (126 mL, 0.63 mol) was added to a stirredsuspension of the compound of Example 48 (180 g, 0.52 mol) in saturatedaqueous sodium chloride (414 mL) at room temperature. The mixture wasstirred at room temperature for 30 minutes, cooled to 10° and stirred atthis temperature for a further 30 minutes. The solid was collected byvacuum filtration, washed with chilled water (2×90 mL) and dried, invacuo, at 33° to give the title compound (81.3 g, 81%).

EXAMPLE 50

(1'R,2'S,S'R)-MENTHTL-5R ACETOXY-1,3-OXATHIOLANE-2R-CARBOXYLATE##STR66##

a) A solution of oxalyl chloride (66.5 g, 0.52 mol) in dichloromethane(120 mL) was added over 30 minutes to a stirred cold (-5°) mixture ofN,N-dimethylformamide (32 mL) and dichloromethane (240 mL), and thesuspension formed was stirred at -5° to 0° for 30 minutes. The compoundof Example 49 (80 g, 0.42 mol) was added in portions and the resultantyellow solution was stirred at 0° for 45 minutes. This solution wasadded over 60 minutes to a stirred, cold (-5°) solution of(1R,2S,5R)-(-)-menthol (65.2 g, 0.425 mol) in dichloromethane (200 mL)and pyridine (84 mL, 1.04 mol) and the resultant suspension was stirredat 0°-5° for a further 2 hours.

The reaction mixture was washed with 2 M-aqueous hydrochloric acid(1×240 mL, 1×160 mL) and the combined aqueous acidic washes were backextracted with dichloromethane (160 mL). The organic phases werecombined, clarified, and concentrated in vacuo to c.a. 240 mL,2,2,4-trimethylpentane (400 mL) was added and the solution concentrated,in vacuo, to 240 mL. Crystallisation of the product occurred during thedistillation. Further 2,2,4-trimethylpentane (400 mL) was added and themixture concentrated to c.a. 700 mL. The stirred suspension was thencooled to 5° and aged for 60 minutes. The solid was collected by vacuumfiltration, washed with 2,2,4-trimethylpentane (2×80 mL) and dried, invacuo, at 33° to give the title compound (93.2 g, 68%) as shown bycomparison of the ¹ H NMR spectrum with that of Example 8.

b) Oxalyl chloride (102 g, 0.80 mol) was added over 20 minutes to astirred, cold (-10°) mixture of N,N-dimethylformamide (63 μL) anddichloromethane (840 mL) and the suspension formed was stirred at -10°to -6° for 15 minutes. The compound of Example B (140 g, 0.728 mol) wasadded and the resultant pale yellow solution was stirred at -8° for 20minutes. (1R,2S,5R)-(-)-Menthol (126 g, 0.80 mol) was added followed bypyridine (140 mL, 1.73 mol), added over 50 minutes. The suspensionformed was stirred at -9° for 18 hours and then 1M aqueous hydrochloricacid (280 mL) was added. The separated aqueous acid phase was extractedwith dichloromethane (140 mL) and the combined organic phases werewashed with 1M aqueous hydrochloric acid (280 mL). The aqueous phase wasback extracted with dichloromethane (140 mL) and the combined organicphases were washed with a solution containing sodium hydrogen carbonate(5.6 g) and sodium chloride (28 g) in water (266 mL). The aqueous phasewas back extracted with dichloromethane (140 mL) and the combinedorganic phases were clarified and concentrated to 560 mL by distillationat atmospheric pressure. 2,2,4-Trimethylpentane (700 mL) was added andthe solution was concentrated, in vacuo, to 700 mL. The2,2,4-trimethylpentane addition/reconcentration procedure was repeated,and the resultant solution was cooled to 17° (seeded with authenticproduct (0.7 g) at 34° and 23°). The suspension was stirred at 17° for 2hours and the solid was collected by vacuum filtration, washed with2,2,4-trimethylpentane (2×70 mL) and dried, in vacuo, at 43° to give thetitle compound (332 g, 14%) as shown by comparison of the ¹ H NMRspectrum with that of Example 8).

While we have presented a number of embodiments of our invention, manyalternatives, modifications and variations of these embodiments will beapparent to those of ordinary skill in the art. Therefore, it will beappreciated that the scope of this invention is to be defined by thefollowing claims, rather than the specific examples presented above.

We claim:
 1. A process for producing an intermediate of formula (IIa) orformula (IIb) ##STR67## wherein W is S, S═O, SO₂, or O; X is S, S═O,SO₂, or O;R₃ is a substituted carbonyl or carbonyl derivative; and L isa leaving group,comprising the step of resolving a mixture of the twocompounds using a chiral auxiliary.
 2. A method of preparing a compoundof formula (IIa') or formula (IIb'): ##STR68## wherein W is S, S=O, SO₂,or O; X is S, S═O, SO₂, or O;R₃ is a substituted carbonyl or carbonylderivative; and L is a leaving group;comprising the step of resolving amixture of the two compounds by means of a chiral auxiliary.
 3. A methodof preparing a compound of formula (IIa") or formula (IIb"): ##STR69##wherein W is S, S═O, SO₂, or O; X is S, S═O, SO₂, or O:R₃ is asubstituted carbonyl or carbonyl derivative; and L is a leavinggroup;comprising the step of resolving a mixture of the two compounds bymeans of a chiral auxiliary.